Acetaminophen-Pregabalin Combinations And Methods Of Treating Pain

ABSTRACT

Compositions and methods for an injectable liquid formulation for reducing consumption or need of a postoperative analgesic compound by a patient are presented. The pharmaceutical formulation can contain a non-opioid analgesic and a gabapentinoid, and can be administered prior to surgery to reduce postoperative pain.

CROSS REFERENCE

This application is a divisional application of our allowed USapplication with the Ser. No. 16/753,042, filed Apr. 2, 2020, which is anational stage application of our International Patent application withthe serial number PCT/US2018/053864, filed Oct. 2, 2018, which claimsthe benefit of U.S. Provisional Application No. 62/567,384, filed Oct.3, 2017, all of which are incorporated herein by reference in itsentirety.

BACKGROUND

Postoperative pain management can involve the use of opioids ornon-steroidal inflammatory drugs (NSAIDs) following surgery. However,the use of opioids or opioid-derived analgesics can lead to undesirableside effects including, for example, nausea, vomiting, constipation, andpoor respiratory function. Thus, an analgesic that could be administeredto a patient prior to surgery could obviate the need for postoperativeadministration of opioids and reduce the occurrence of unwanted sideeffects.

INCORPORATION BY REFERENCE

Each patent, publication, and non-patent literature cited in theapplication is hereby incorporated by reference in its entirety as ifeach was incorporated by reference individually.

SUMMARY

In some embodiments, the invention provides a pharmaceutical compositioncomprising, in a liquid unit dosage form: a) a gabapentinoid; b)acetaminophen; c) a pH-adjusting agent; and d) water.

In some embodiments, the invention provides a method of treating pain ina subject in need thereof, the method comprising administering to thesubject a therapeutically-effective amount of a liquid unit dosage form,wherein the liquid unit dosage form comprises: a) a gabapentinoid; b)acetaminophen; c) a pH-adjusting agent; and d) water.

In some embodiments, the invention provides a method of manufacturing apharmaceutical formulation, the method comprising: a) adding water to amanufacturing tank; b) deoxygenating the water in the manufacturing tankby sparging nitrogen to achieve a dissolved oxygen level of less thanabout 1 ppm; c) adding a buffer to the water in the manufacturing tankto provide a mixture; d) adding a pH-adjusting agent to the mixture inthe manufacturing tank, wherein the adding the pH-adjusting agent to themixture in the manufacturing tank adjusts a pH of the mixture to aboutpH 4 to about pH 7; e) disposing a gabapentinoid into the mixture in themanufacturing tank; and f) disposing acetaminophen into the mixture inthe manufacturing tank.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows a graph of plasma concentration of acetaminophen eitheradministered alone or in combination with pregabalin after intravenousadministration.

FIG. 2 shows a graph of plasma concentration of pregabalin eitheradministered alone or in combination with acetaminophen afterintravenous administration.

FIG. 3 shows a graph of the effects of increasing pregabalin doses onmotor control in a rat model after oral administration of pregabalin.

FIG. 4 shows a graph of effects of pregabalin in the presence or absenceof acetaminophen on motor control in a rat model after intravenousadministration of pregabalin.

FIG. 5 shows a graph of effects of pregabalin in the presence or absenceof acetaminophen on somatic pain in a rat model after intravenousadministration.

DETAILED DESCRIPTION

The present application relates to pharmaceutical formulations that canbe used to relieve postoperative pain in a subject in need thereof.After surgery, patients can suffer from severe pain that can persist fordays, weeks, or months. Postoperative pain can be managed byadministering to the patient, for example, centrally-acting μ-opioidanalgesics or NSAIDs. However, the occurrence of undesirable sideeffects can lead to reduced patient compliance and ineffective paintreatment. The present application describes a pharmaceuticalformulation and methods of use thereof to alleviate postoperative painby, for example, preoperatively administering the pharmaceuticalformulation to the patient. A pharmaceutical formulation describedherein can also reduce postoperative opioid consumption by a patient whohas been administered the pharmaceutical formulation.

Pain.

The present disclosure provides pharmaceutical compositions for thetreatment of pain. Pain can be, for example, mild, moderate, severe, oragonizing. The pain of a subject can be assessed using a numeric scale,in which a patient can self-report pain on a scale from 0-10, where 0indicates no pain, 1-3 suggests mild pain, 4-6 indicates moderate pain,and 7-10 suggests severe and disabling pain.

Pain can include, for example, angina pain, bone injury pain, centralpain, chronic lower back pain, cluster headaches, dental pain,genitourinary tract-related pain including cystitis and nociceptivepain, herpes neuralgia, migraine, neuropathic pain, pain during laborand delivery, pain resulting from burns, phantom limb pain,postoperative pain, postpartum pain, surgical pain, or visceral pain. Insome embodiments, the pain is postoperative pain.

The pain can be chronic or acute. Postoperative pain can describe thatoccurs after a surgery, and can be a direct or indirect result of thesurgery.

A pharmaceutical formulation described herein can be administered to thepatient during or prior to surgery to treat, for example, acutepostoperative pain. The postoperative pain can be reduced by at leastabout 10%, at least about 15%, at least about 20%, at least about 25%,at least about 30%, at least about 35%, at least about 40%, at leastabout 45%, at least about 50%, at least about 60%, at least about 70%,at least about 80%, at least about 90%, or at least about 99%. Thereduction is postoperative pain can happen after about 10 minutes, about20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours,about 6 hours, about 8 hours, about 10 hours, or about 12 hours afterthe surgery.

Non-Opioid Analgesic.

The present disclosure provides pharmaceutical formulations containing,for example, a non-opioid analgesic. A non-opioid analgesic can include,for example, an NSAID, an anti-depressant, a gabapentinoid, ananti-convulsant, an anti-pyretic, acetylsalicylic acid, or acetaminophen(N-(4-hydroxyphenyl)acetamide); paracetamol; N-acetyl-para-aminophenol).Acetaminophen is an anti-pyretic agent, and can be used to treat mild tomoderate pain in adults and children.

In some embodiments, a non-opioid analgesic in a pharmaceuticalformulation described herein is acetaminophen. In some embodiments, anon-opioid analgesic in a pharmaceutical formulation described herein isa gabapentinoid. In some embodiments, a pharmaceutical formulationdescribed herein contains acetaminophen and a gabapentinoid.

The non-opioid analgesic can be, for example, aceclofenac, acemetacin,acetaminophen, acetylsalicylic acid, amoxiprin, azapropazone,benorilate, bromfenac, carprofen, choline magnesium salicylate,diflunisal, diclofenac, etodolac, faislamine, fenbuprofen, flubiprofen,gabapentin, ibuprofen, indometacin, ketaprofen, ketorolac, lomoxicam,loxoprofen, magnesium salicylate, meclofenamic, mefenamic acid,meloxicam, metamizole, methyl salicylate, nabumetone, naproxen,oxyphenbutazone, piroxicam, phenylbutazone, pregabalin, sulfinprazone,sulindac, suprofen, tenoxicam, tolmetin, or a pharmaceuticallyacceptable salt of any of the foregoing, or any combination thereof.

Gabapentinoids.

Gabapentinoids are a class of compounds that are derivatives ofy-aminobutyric acid (GABA). Gabapentinoids can block the α₂δ subunit(gabapentin receptor)-containing voltage-dependent calcium channels(VDCC). Upon binding of the gabapentinoid to the α₂δ subunit-containingVDCCs, the gabapentinoid can inhibit the action of the VDCC.Gabapentinoids demonstrate similar affinity to the two subunits (α₂δ-1and α₂δ-2) of the α₂δ portion of the VDCC. A gabapentinoid can include,for example, gabapentin and pregabalin (3-isobutyl-γ-aminobutyric acid).

Pregabalin is (3S)-3-(Aminomethyl)-5-methylhexanoic acid, and is ay-aminobutyric acid analogue, with anticonvulsant, anxiolytic, andsleep-modulating properties. Pregabalin can treat, for example, acutepain, chronic pain, neuropathic pain, incisional injury, andinflammatory injury. Additionally, pregabalin can be used to reduceacute postoperative pain when the pregabalin is administered to thepatient preoperatively.

A pharmaceutical formulation described herein can contain, for example,pregabalin. The pharmaceutical formulation can further contain, forexample, acetaminophen.

Pharmaceutically-Acceptable Salts.

The present disclosure provides the use of pharmaceutically-acceptablesalts of any compound described herein. Pharmaceutically-acceptablesalts include, for example, acid-addition salts and base-addition salts.The acid that is added to the compound to form an acid-addition salt canbe an organic acid or an inorganic acid. A base that is added to thecompound to form a base-addition salt can be an organic base or aninorganic base. In some embodiments, a pharmaceutically-acceptable saltis a metal salt.

Metal salts can arise from the addition of an inorganic base to acompound described herein. The inorganic base consists of a metal cationpaired with a basic counterion, such as, for example, hydroxide,carbonate, bicarbonate, or phosphate. The metal can be an alkali metal,alkaline earth metal, transition metal, or main group metal. In someembodiments, the metal is lithium, sodium, potassium, cesium, cerium,magnesium, manganese, iron, calcium, strontium, cobalt, titanium,aluminum, copper, cadmium, or zinc.

In some embodiments, a metal salt is a lithium salt, a sodium salt, apotassium salt, a cesium salt, a cerium salt, a magnesium salt, amanganese salt, an iron salt, a calcium salt, a strontium salt, a cobaltsalt, a titanium salt, an aluminum salt, a copper salt, a cadmium salt,or a zinc salt.

Ammonium salts can arise from the addition of ammonia or an organicamine to a compound described herein. In some embodiments, the organicamine is triethyl amine, diisopropyl amine, ethanol amine, diethanolamine, triethanol amine, morpholine, N-methylmorpholine, piperidine,N-methylpiperidine, N-ethylpiperidine, dibenzylamine, piperazine,pyridine, pyrrazole, piprazole, imidazole, or pyrazine.

In some embodiments, an ammonium salt is a triethyl amine salt, adiisopropyl amine salt, an ethanol amine salt, a diethanol amine salt, atriethanol amine salt, a morpholine salt, an N-methylmorpholine salt, apiperidine salt, an N-methylpiperidine salt, an N-ethylpiperidine salt,a dibenzylamine salt, a piperazine salt, a pyridine salt, a pyrrazolesalt, a piprazole salt, an imidazole salt, or a pyrazine salt.

Acid addition salts can arise from the addition of an acid to a compounddescribed herein. In some embodiments, the acid is organic. In someembodiments, the acid is inorganic. In some embodiments, the acid ishydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid,nitrous acid, sulfuric acid, sulfurous acid, a phosphoric acid,isonicotinic acid, lactic acid, salicylic acid, tartaric acid, ascorbicacid, gentisinic acid, gluconic acid, glucaronic acid, saccaric acid,formic acid, benzoic acid, glutamic acid, pantothenic acid, acetic acid,propionic acid, butyric acid, fumaric acid, succinic acid,methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, citric acid, oxalic acid, or maleic acid.

In some embodiments, the salt is a hydrochloride salt, a hydrobromidesalt, a hydroiodide salt, a nitrate salt, a nitrite salt, a sulfatesalt, a sulfite salt, a phosphate salt, isonicotinate salt, a lactatesalt, a salicylate salt, a tartrate salt, an ascorbate salt, agentisinate salt, a gluconate salt, a glucaronate salt, a saccaratesalt, a formate salt, a benzoate salt, a glutamate salt, a pantothenatesalt, an acetate salt, a propionate salt, a butyrate salt, a fumaratesalt, a succinate salt, a methanesulfonate salt, an ethanesulfonatesalt, a benzenesulfonate salt, a p-toluenesulfonate salt, a citratesalt, an oxalate salt, or a maleate salt.

Formulations.

A pharmaceutical formulation of the disclosure can provide atherapeutically-effective amount of any compound disclosed herein. Apharmaceutical formulation of the disclosure can provide atherapeutically-effective amount of a gabapentinoid and an additionalnon-opioid analgesic. In some embodiments, the gabapentinoid ispregabalin. In some embodiments, the additional non-opioid analgesic isacetaminophen.

The disclosed formulations can contain one or morepharmaceutically-acceptable agents, which alone or in combinationsolubilize a compound herein or a pharmaceutically-acceptable saltthereof. In some embodiments, the pharmaceutically-acceptable agent is abuffer. In some embodiments, the pharmaceutically-acceptable agent is acitrate buffer. In some embodiments, the pharmaceutically-acceptableagent is a phosphate buffer. In some embodiments, thepharmaceutically-acceptable agent is an acetate buffer. A buffer asdescribed herein can be formed from a solution containing, for example,an acid and a conjugate base of the acid, or a base and a conjugate acidof the base. The acid in a buffer described herein can be a weak acid. Abase in a buffer described herein can be a weak base. Any formulationdescribed herein can contain, for example, an acid, and a conjugate baseof the acid, or a base, and a conjugate acid of the base.

A formulation described herein can contain an isotonicity inducingagent. The isotonicity inducing agent can be, for example, sodiumchloride or mannitol.

In some embodiments, a compound disclosed herein orpharmaceutically-acceptable salt thereof is present in a formulation inan amount of from about 0.1 mg/mL to about 100 mg/mL, from about 0.1mg/mL to about 1 mg/mL, from about 0.1 mg/mL to about 5 mg/mL, fromabout 5 mg/mL to about 10 mg/mL, from about 10 mg/mL to about 15 mg/mL,from about 15 mg/mL to about 20 mg/mL, from about 20 mg/mL to about 25mg/mL, from about 25 mg/mL to about 30 mg/mL, from about 30 mg/mL toabout 35 mg/mL, from about 35 mg/mL to about 40 mg/mL, from about 40mg/mL to about 45 mg/mL, about 45 mg/mL to about 50 mg/mL, from about 50mg/mL to about 55 mg/mL, from about 55 mg/mL to about 60 mg/mL, fromabout 60 mg/mL to about 65 mg/mL, from about 65 mg/mL to about 70 mg/mL,from about 70 mg/mL to about 75 mg/mL, about 75 mg/mL to about 80 mg/mL,from about 80 mg/mL to about 85 mg/mL, from about 85 mg/mL to about 90mg/mL, from about 90 mg/mL to about 95 mg/mL, or from about 95 mg/mL toabout 100 mg/mL. The compound can be, for example, acetaminophen orpregabalin.

In some embodiments, a compound disclosed herein orpharmaceutically-acceptable salt thereof is present in a formulation inan amount of about 1 mg/mL, about 2 mg/mL, about 3 mg/mL, about 4 mg/mL,about 5 mg/mL, about 6 mg/mL, about 7 mg/mL, about 8 mg/mL, about 9mg/mL, about 10 mg/mL, about 11 mg/mL about 12 mg/mL, about 13 mg/mL,about 14 mg/mL, about 15 mg/mL, about 16 mg/mL, about 17 mg/mL, about 18mg/mL, about 19 mg/mL, about 20 mg/mL, about 21 mg/mL about 22 mg/mL,about 23 mg/mL, about 24 mg/mL, about 25 mg/mL, about 26 mg/mL, about 27mg/mL, about 28 mg/mL, about 29 mg/mL, about 30 mg/mL, about 31 mg/mLabout 32 mg/mL, about 33 mg/mL, about 34 mg/mL, about 35 mg/mL, about 36mg/mL, about 37 mg/mL, about 38 mg/mL, about 39 mg/mL, about 40 mg/mL,about 41 mg/mL about 42 mg/mL, about 43 mg/mL, about 44 mg/mL, about 45mg/mL, about 46 mg/mL, about 47 mg/mL, about 48 mg/mL, about 49 mg/mL,about 50 mg/mL, about 51 mg/mL about 52 mg/mL, about 53 mg/mL, about 54mg/mL, about 55 mg/mL, about 56 mg/mL, about 57 mg/mL, about 58 mg/mL,about 59 mg/mL, about 60 mg/mL, about 61 mg/mL about 62 mg/mL, about 63mg/mL, about 64 mg/mL, about 65 mg/mL, about 66 mg/mL, about 67 mg/mL,about 68 mg/mL, about 69 mg/mL, about 70 mg/mL, about 71 mg/mL about 72mg/mL, about 73 mg/mL, about 74 mg/mL, about 75 mg/mL, about 76 mg/mL,about 77 mg/mL, about 78 mg/mL, about 79 mg/mL, about 80 mg/mL, about 81mg/mL about 82 mg/mL, about 83 mg/mL, about 84 mg/mL, about 85 mg/mL,about 86 mg/mL, about 87 mg/mL, about 88 mg/mL, about 89 mg/mL, about 90mg/mL, about 91 mg/mL about 92 mg/mL, about 93 mg/mL, about 94 mg/mL,about 95 mg/mL, about 96 mg/mL, about 97 mg/mL, about 98 mg/mL, about 99mg/mL, or about 100 mg/mL. The compound can be, for example,acetaminophen or pregabalin.

A pharmaceutical formulation described herein can contain, for example,acetaminophen, pregabalin, sodium chloride, and citric acid monohydrate.The pharmaceutical formulation can be at, for example, pH 5, 5.5, or 6.In some embodiments, the pH of the pharmaceutical formulation is 5.5. Insome embodiments, the pH of the pharmaceutical formulation is 6. Theacetaminophen can be present in the pharmaceutical formulation at aconcentration of about 5 mg/mL, about 6 mg/mL, about 7 mg/mL, about 8mg/mL, about 9 mg/mL, or about 10 mg/mL. In some embodiments, theacetaminophen is present in the pharmaceutical formulation at aconcentration of 10 mg/mL. The pregabalin can be present in thepharmaceutical formulation a concentration of about 4 mg/mL, about 4.5mg/ml, or about 5 mg/mL. In some embodiments, the pregabalin is presentin the pharmaceutical formulation at a concentration of 4.5 mg/mL. Thesodium chloride can be present in the pharmaceutical formulation at aconcentration of about 4 mg/mL, about 4.5 mg/mL, about 5 mg/mL, about5.5 mg/mL, or about 6 mg/mL. In some embodiments, the sodium chloride ispresent in the pharmaceutical formulation at a concentration of 5 mg/mL.In some embodiments, the sodium chloride is present in thepharmaceutical formulation at a concentration of 4.5 mg/mL. The citricacid monohydrate can be present in the pharmaceutical formulation at aconcentration of about 2 mg/mL, about 2.05 mg/mL, about 2.1 mg/mL, about2.101 mg/mL, about 2.102 mg/mL, about 2.103 mg/mL, about 2.014 mg/mL,about 2.105 mg/mL, about 2.11 mg/mL, about 2.15 mg/mL, or about 2.2mg/mL. In some embodiments, the citric acid monohydrate is present inthe pharmaceutical formulation at a concentration of 2.101 mg/mL.

A pharmaceutical formulation described herein can contain, for example,acetaminophen, pregabalin, sodium chloride, and acetic acid. Thepharmaceutical formulation can be at, for example, pH 5, 5.5, or 6. Insome embodiments, the pH of the pharmaceutical formulation is 5.5. Theacetaminophen can be present in the pharmaceutical formulation at aconcentration of about 5 mg/mL, about 6 mg/mL, about 7 mg/mL, about 8mg/mL, about 9 mg/mL, or about 10 mg/mL. In some embodiments, theacetaminophen is present in the pharmaceutical formulation at aconcentration of 10 mg/mL. The pregabalin can be present in thepharmaceutical formulation a concentration of about 4 mg/mL, about 4.5mg/ml, or about 5 mg/mL. In some embodiments, the pregabalin is presentin the pharmaceutical formulation at a concentration of 4.5 mg/mL. Thesodium chloride can be present in the pharmaceutical formulation at aconcentration of about 4 mg/mL, about 4.5 mg/mL, about 5 mg/mL, about5.5 mg/mL, or about 6 mg/mL. In some embodiments, the sodium chloride ispresent in the pharmaceutical formulation at a concentration of 5 mg/mL.The acetic acid can be present in the pharmaceutical formulation at aconcentration of about 0.5 mg/mL, about 0.6 mg/mL, about 0.7 mg/mL,about 0.8 mg/mL, about 0.9 mg/mL, or about 1 mg/mL. In some embodiments,the acetic acid is present in the pharmaceutical formulation at aconcentration of 0.6 mg/mL.

A pharmaceutical formulation described herein can contain, for example,acetaminophen, pregabalin, sodium chloride, and sodium dihydrogenphosphate. The pharmaceutical formulation can be at, for example, pH 5,5.5, or 6. In some embodiments, the pH of the pharmaceutical formulationis 6. The acetaminophen can be present in the pharmaceutical formulationat a concentration of about 5 mg/mL, about 6 mg/mL, about 7 mg/mL, about8 mg/mL, about 9 mg/mL, or about 10 mg/mL. In some embodiments, theacetaminophen is present in the pharmaceutical formulation at aconcentration of 10 mg/mL. The pregabalin can be present in thepharmaceutical formulation a concentration of about 4 mg/mL, about 4.5mg/ml, or about 5 mg/mL. In some embodiments, the pregabalin is presentin the pharmaceutical formulation at a concentration of 4.5 mg/mL. Thesodium chloride can be present in the pharmaceutical formulation at aconcentration of about 4 mg/mL, about 4.5 mg/mL, about 5 mg/mL, about5.5 mg/mL, or about 6 mg/mL. In some embodiments, the sodium chloride ispresent in the pharmaceutical formulation at a concentration of 5.5mg/mL. The sodium dihydrogen phosphate can be present in thepharmaceutical formulation at a concentration of about 1 mg/mL, about1.1 mg/mL, about 1.2 mg/mL, about 1.3 mg/mL, about 1.4 mg/mL, about 1.5mg/mL, about 1.6 mg/mL, about 1.7 mg/mL, about 1.8 mg/mL, about 1.9mg/mL, or about 2 mg/mL. In some embodiments, the sodium dihydrogenphosphate is present in the pharmaceutical formulation at aconcentration of 1.2 mg/mL.

Sodium chloride can be a present in a pharmaceutical formulationdescribed herein at a concentration of about 0.1 mg/mL, about 0.2 mg/mL,about 0.3 mg/mL, about 0.4 mg/mL, about 0.5 mg/mL, about 0.6 mg/mL,about 0.7 mg/mL, about 0.8 mg/mL, about 0.9 mg/mL, about 1 mg/mL, about1.1 mg/mL, about 1.2 mg/mL, about 1.3 mg/mL, about 1.4 mg/mL, about 1.5mg/mL, about 1.6 mg/mL, about 1.7 mg/mL, about 1.8 mg/mL, about 1.9mg/mL, about 2 mg/mL, about 2.1 mg/mL, about 2.2 mg/mL, about 2.3 mg/mL,about 2.4 mg/mL, about 2.5 mg/mL, about 2.6 mg/mL, about 2.7 mg/mL,about 2.8 mg/mL, about 2.9 mg/mL, about 3 mg/mL, about 3.1 mg/mL, about3.2 mg/mL, about 3.3 mg/mL, about 3.4 mg/mL, about 3.5 mg/mL, about 3.6mg/mL, about 3.7 mg/mL, about 3.8 mg/mL, about 3.9 mg/mL, about 4 mg/mL,about 4.1 mg/mL, about 4.2 mg/mL, about 4.3 mg/mL, about 4.4 mg/mL,about 4.5 mg/mL, about 4.6 mg/mL, about 4.7 mg/mL, about 4.8 mg/mL,about 4.9 mg/mL, about 5 mg/mL, about 5.1 mg/mL, about 5.2 mg/mL, about5.3 mg/mL, about 5.4 mg/mL, about 5.5 mg/mL, about 5.6 mg/mL, about 5.7mg/mL, about 5.8 mg/mL, about 5.9 mg/mL, or about 6 mg/mL. Sodiumchloride can be present in a pharmaceutical formulation described hereinat a concentration from about 0.1 mg/mL to about 0.5 mg/mL, about 0.2mg/mL to about 0.6 mg/mL, about 0.3 mg/mL to about 0.7 mg/mL, about 0.4mg/mL to about 0.8 mg/mL, about 0.5 mg/mL to about 1 mg/mL, about 0.6mg/mL to about 1.1 mg/mL, about 0.7 mg/mL to about 1.2 mg/mL, about 0.8mg/mL to about 1.3 mg/mL, about 0.9 mg/mL to about 1.4 mg/mL, about 1mg/mL to about 1.5 mg/mL, about 1.1 mg/mL to about 1.6 mg/mL, about 1.2mg/mL to about 1.7 mg/mL, about 1.3 mg/mL to about 1.8 mg/mL, about 1.4mg/mL to about 1.9 mg/mL, about 1.5 mg/mL to about 2 mg/mL, about 1.6mg/mL to about 2.1 mg/mL, about 2.2 mg/mL to about 2.7 mg/mL, about 2.3mg/mL to about 2.8 mg/mL, about 2.4 mg/mL to about 2.9 mg/mL, about 2.5mg/mL to about 3 mg/mL, about 2.6 mg/mL, about 3.1 mg/mL, about 2.7mg/mL to about 3.2 mg/mL, about 2.8 mg/mL to about 3.3 mg/mL, about 2.9mg/mL to about 3.4 mg/mL, about 3 mg/mL to about 3.5 mg/mL, about 3.1mg/mL to about 3.6 mg/mL, about 3.2 mg/mL to about 3.7 mg/mL, about 3.3mg/mL to about 3.8 mg/mL, about 3.4 mg/mL to about 3.9 mg/mL, about 3.5mg/mL to about 4 mg/mL, about 3.6 mg/mL to about 4.1 mg/mL, about 3.7mg/mL to about 4.2 mg/mL, about 3.8 mg/mL to about 4.3 mg/mL, about 3.9mg/mL to about 4.4 mg/mL, about 4 mg/mL to about 4.5 mg/mL, about 4.1mg/mL to about 4.6 mg/mL, about 4.2 mg/mL to about 4.7 mg/mL, about 4.3mg/mL to about 4.8 mg/mL, about 4.4 mg/mL to about 4.9 mg/mL, about 4.5mg/mL to about 5 mg/mL, about 4.6 mg/mL to about 5.1 mg/mL, about 4.7mg/mL to about 5.2 mg/mL, about 4.8 mg/mL to about 5.3 mg/mL, about 4.9mg/mL to about 5.4 mg/mL, about 5 mg/mL to about 5.5 mg/mL, about 5.1mg/mL to about 5.6 mg/mL, about 5.2 mg/mL to about 5.7 mg/mL, about 5.3mg/mL to about 5.8 mg/mL, about 5.4 mg/mL to about 5.9 mg/mL, or about5.5 mg/mL to about 6 mg/mL.

L-Histidine can be a present in a pharmaceutical formulation describedherein at a concentration of about 0.1 mg/mL, about 0.2 mg/mL, about 0.3mg/mL, about 0.4 mg/mL, about 0.5 mg/mL, about 0.6 mg/mL, about 0.7mg/mL, about 0.8 mg/mL, about 0.9 mg/mL, about 1 mg/mL, about 1.1 mg/mL,about 1.2 mg/mL, about 1.3 mg/mL, about 1.4 mg/mL, about 1.5 mg/mL,about 1.6 mg/mL, about 1.7 mg/mL, about 1.8 mg/mL, about 1.9 mg/mL,about 2 mg/mL, about 2.1 mg/mL, about 2.2 mg/mL, about 2.3 mg/mL, about2.4 mg/mL, about 2.5 mg/mL, about 2.6 mg/mL, about 2.7 mg/mL, about 2.8mg/mL, about 2.9 mg/mL, about 3 mg/mL, about 3.1 mg/mL, about 3.2 mg/mL,about 3.3 mg/mL, about 3.4 mg/mL, about 3.5 mg/mL, about 3.6 mg/mL,about 3.7 mg/mL, about 3.8 mg/mL, about 3.9 mg/mL, about 4 mg/mL, about4.1 mg/mL, about 4.2 mg/mL, about 4.3 mg/mL, about 4.4 mg/mL, about 4.5mg/mL, about 4.6 mg/mL, about 4.7 mg/mL, about 4.8 mg/mL, about 4.9mg/mL, about 5 mg/mL, about 5.1 mg/mL, about 5.2 mg/mL, about 5.3 mg/mL,about 5.4 mg/mL, about 5.5 mg/mL, about 5.6 mg/mL, about 5.7 mg/mL,about 5.8 mg/mL, about 5.9 mg/mL, or about 6 mg/mL. L-Histidine can bepresent in a pharmaceutical formulation described herein at aconcentration from about 0.1 mg/mL to about 0.5 mg/mL, about 0.2 mg/mLto about 0.6 mg/mL, about 0.3 mg/mL to about 0.7 mg/mL, about 0.4 mg/mLto about 0.8 mg/mL, about 0.5 mg/mL to about 1 mg/mL, about 0.6 mg/mL toabout 1.1 mg/mL, about 0.7 mg/mL to about 1.2 mg/mL, about 0.8 mg/mL toabout 1.3 mg/mL, about 0.9 mg/mL to about 1.4 mg/mL, about 1 mg/mL toabout 1.5 mg/mL, about 1.1 mg/mL to about 1.6 mg/mL, about 1.2 mg/mL toabout 1.7 mg/mL, about 1.3 mg/mL to about 1.8 mg/mL, about 1.4 mg/mL toabout 1.9 mg/mL, about 1.5 mg/mL to about 2 mg/mL, about 1.6 mg/mL toabout 2.1 mg/mL, about 2.2 mg/mL to about 2.7 mg/mL, about 2.3 mg/mL toabout 2.8 mg/mL, about 2.4 mg/mL to about 2.9 mg/mL, about 2.5 mg/mL toabout 3 mg/mL, about 2.6 mg/mL, about 3.1 mg/mL, about 2.7 mg/mL toabout 3.2 mg/mL, about 2.8 mg/mL to about 3.3 mg/mL, about 2.9 mg/mL toabout 3.4 mg/mL, about 3 mg/mL to about 3.5 mg/mL, about 3.1 mg/mL toabout 3.6 mg/mL, about 3.2 mg/mL to about 3.7 mg/mL, about 3.3 mg/mL toabout 3.8 mg/mL, about 3.4 mg/mL to about 3.9 mg/mL, about 3.5 mg/mL toabout 4 mg/mL, about 3.6 mg/mL to about 4.1 mg/mL, about 3.7 mg/mL toabout 4.2 mg/mL, about 3.8 mg/mL to about 4.3 mg/mL, about 3.9 mg/mL toabout 4.4 mg/mL, about 4 mg/mL to about 4.5 mg/mL, about 4.1 mg/mL toabout 4.6 mg/mL, about 4.2 mg/mL to about 4.7 mg/mL, about 4.3 mg/mL toabout 4.8 mg/mL, about 4.4 mg/mL to about 4.9 mg/mL, about 4.5 mg/mL toabout 5 mg/mL, about 4.6 mg/mL to about 5.1 mg/mL, about 4.7 mg/mL toabout 5.2 mg/mL, about 4.8 mg/mL to about 5.3 mg/mL, about 4.9 mg/mL toabout 5.4 mg/mL, about 5 mg/mL to about 5.5 mg/mL, about 5.1 mg/mL toabout 5.6 mg/mL, about 5.2 mg/mL to about 5.7 mg/mL, about 5.3 mg/mL toabout 5.8 mg/mL, about 5.4 mg/mL to about 5.9 mg/mL, or about 5.5 mg/mLto about 6 mg/mL.

Citric acid monohydrate or sodium dihydrogen phosphate can be a presentin a pharmaceutical formulation described herein at a concentration ofabout 0.1 mg/mL, about 0.2 mg/mL, about 0.3 mg/mL, about 0.4 mg/mL,about 0.5 mg/mL, about 0.6 mg/mL, about 0.7 mg/mL, about 0.8 mg/mL,about 0.9 mg/mL, about 1 mg/mL, about 1.1 mg/mL, about 1.2 mg/mL, about1.3 mg/mL, about 1.4 mg/mL, about 1.5 mg/mL, about 1.6 mg/mL, about 1.7mg/mL, about 1.8 mg/mL, about 1.9 mg/mL, about 2 mg/mL, about 2.1 mg/mL,about 2.2 mg/mL, about 2.3 mg/mL, about 2.4 mg/mL, about 2.5 mg/mL,about 2.6 mg/mL, about 2.7 mg/mL, about 2.8 mg/mL, about 2.9 mg/mL,about 3 mg/mL, about 3.1 mg/mL, about 3.2 mg/mL, about 3.3 mg/mL, about3.4 mg/mL, about 3.5 mg/mL, about 3.6 mg/mL, about 3.7 mg/mL, about 3.8mg/mL, about 3.9 mg/mL, about 4 mg/mL, about 4.1 mg/mL, about 4.2 mg/mL,about 4.3 mg/mL, about 4.4 mg/mL, about 4.5 mg/mL, about 4.6 mg/mL,about 4.7 mg/mL, about 4.8 mg/mL, about 4.9 mg/mL, about 5 mg/mL, about5.1 mg/mL, about 5.2 mg/mL, about 5.3 mg/mL, about 5.4 mg/mL, about 5.5mg/mL, about 5.6 mg/mL, about 5.7 mg/mL, about 5.8 mg/mL, about 5.9mg/mL, or about 6 mg/mL. Citric acid monohydrate or sodium dihydrogenphosphate can be present in a pharmaceutical formulation describedherein at a concentration from about 0.1 mg/mL to about 0.5 mg/mL, about0.2 mg/mL to about 0.6 mg/mL, about 0.3 mg/mL to about 0.7 mg/mL, about0.4 mg/mL to about 0.8 mg/mL, about 0.5 mg/mL to about 1 mg/mL, about0.6 mg/mL to about 1.1 mg/mL, about 0.7 mg/mL to about 1.2 mg/mL, about0.8 mg/mL to about 1.3 mg/mL, about 0.9 mg/mL to about 1.4 mg/mL, about1 mg/mL to about 1.5 mg/mL, about 1.1 mg/mL to about 1.6 mg/mL, about1.2 mg/mL to about 1.7 mg/mL, about 1.3 mg/mL to about 1.8 mg/mL, about1.4 mg/mL to about 1.9 mg/mL, about 1.5 mg/mL to about 2 mg/mL, about1.6 mg/mL to about 2.1 mg/mL, about 2.2 mg/mL to about 2.7 mg/mL, about2.3 mg/mL to about 2.8 mg/mL, about 2.4 mg/mL to about 2.9 mg/mL, about2.5 mg/mL to about 3 mg/mL, about 2.6 mg/mL, about 3.1 mg/mL, about 2.7mg/mL to about 3.2 mg/mL, about 2.8 mg/mL to about 3.3 mg/mL, about 2.9mg/mL to about 3.4 mg/mL, about 3 mg/mL to about 3.5 mg/mL, about 3.1mg/mL to about 3.6 mg/mL, about 3.2 mg/mL to about 3.7 mg/mL, about 3.3mg/mL to about 3.8 mg/mL, about 3.4 mg/mL to about 3.9 mg/mL, about 3.5mg/mL to about 4 mg/mL, about 3.6 mg/mL to about 4.1 mg/mL, about 3.7mg/mL to about 4.2 mg/mL, about 3.8 mg/mL to about 4.3 mg/mL, about 3.9mg/mL to about 4.4 mg/mL, about 4 mg/mL to about 4.5 mg/mL, about 4.1mg/mL to about 4.6 mg/mL, about 4.2 mg/mL to about 4.7 mg/mL, about 4.3mg/mL to about 4.8 mg/mL, about 4.4 mg/mL to about 4.9 mg/mL, about 4.5mg/mL to about 5 mg/mL, about 4.6 mg/mL to about 5.1 mg/mL, about 4.7mg/mL to about 5.2 mg/mL, about 4.8 mg/mL to about 5.3 mg/mL, about 4.9mg/mL to about 5.4 mg/mL, about 5 mg/mL to about 5.5 mg/mL, about 5.1mg/mL to about 5.6 mg/mL, about 5.2 mg/mL to about 5.7 mg/mL, about 5.3mg/mL to about 5.8 mg/mL, about 5.4 mg/mL to about 5.9 mg/mL, or about5.5 mg/mL to about 6 mg/mL.

Acetic acid can be present in a pharmaceutical formulation describedherein at a concentration of about 0.1 mg/mL, about 0.2 mg/mL, about 0.3mg/mL, about 0.4 mg/mL, about 0.5 mg/mL, about 0.6 mg/mL, about 0.7mg/mL, about 0.8 mg/mL, about 0.9 mg/mL, about 1 mg/mL, about 1.1 mg/mL,about 1.2 mg/mL, about 1.3 mg/mL, about 1.4 mg/mL, about 1.5 mg/mL,about 1.6 mg/mL, about 1.7 mg/mL, about 1.8 mg/mL, about 1.9 mg/mL,about 2 mg/mL, about 2.1 mg/mL, about 2.2 mg/mL, about 2.3 mg/mL, about2.4 mg/mL, about 2.5 mg/mL, about 2.6 mg/mL, about 2.7 mg/mL, about 2.8mg/mL, about 2.9 mg/mL, about 3 mg/mL, about 3.1 mg/mL, about 3.2 mg/mL,about 3.3 mg/mL, about 3.4 mg/mL, about 3.5 mg/mL, about 3.6 mg/mL,about 3.7 mg/mL, about 3.8 mg/mL, about 3.9 mg/mL, about 4 mg/mL, about4.1 mg/mL, about 4.2 mg/mL, about 4.3 mg/mL, about 4.4 mg/mL, about 4.5mg/mL, about 4.6 mg/mL, about 4.7 mg/mL, about 4.8 mg/mL, about 4.9mg/mL, or about 5 mg/mL. Acetic acid can be present in a pharmaceuticalformulation described herein at a concentration of about 0.1 mg/mL toabout 0.5 mg/mL, about 0.2 mg/mL to about 0.6 mg/mL, about 0.3 mg/mL toabout 0.7 mg/mL, about 0.4 mg/mL to about 0.8 mg/mL, about 0.5 mg/mL toabout 1 mg/mL, about 0.6 mg/mL to about 1.1 mg/mL, about 0.7 mg/mL toabout 1.2 mg/mL, about 0.8 mg/mL to about 1.3 mg/mL, about 0.9 mg/mL toabout 1.4 mg/mL, about 1 mg/mL to about 1.5 mg/mL, about 1.1 mg/mL toabout 1.6 mg/mL, about 1.2 mg/mL to about 1.7 mg/mL, about 1.3 mg/mL toabout 1.8 mg/mL, about 1.4 mg/mL to about 1.9 mg/mL, about 1.5 mg/mL toabout 2 mg/mL, about 1.6 mg/mL to about 2.1 mg/mL, about 2.2 mg/mL toabout 2.7 mg/mL, about 2.3 mg/mL to about 2.8 mg/mL, about 2.4 mg/mL toabout 2.9 mg/mL, about 2.5 mg/mL to about 3 mg/mL, about 2.6 mg/mL,about 3.1 mg/mL, about 2.7 mg/mL to about 3.2 mg/mL, about 2.8 mg/mL toabout 3.3 mg/mL, about 2.9 mg/mL to about 3.4 mg/mL, about 3 mg/mL toabout 3.5 mg/mL, about 3.1 mg/mL to about 3.6 mg/mL, about 3.2 mg/mL toabout 3.7 mg/mL, about 3.3 mg/mL to about 3.8 mg/mL, about 3.4 mg/mL toabout 3.9 mg/mL, about 3.5 mg/mL to about 4 mg/mL, about 3.6 mg/mL toabout 4.1 mg/mL, about 3.7 mg/mL to about 4.2 mg/mL, about 3.8 mg/mL toabout 4.3 mg/mL, about 3.9 mg/mL to about 4.4 mg/mL, about 4 mg/mL toabout 4.5 mg/mL, about 4.1 mg/mL to about 4.6 mg/mL, about 4.2 mg/mL toabout 4.7 mg/mL, about 4.3 mg/mL to about 4.8 mg/mL, about 4.4 mg/mL toabout 4.9 mg/mL, or about 4.5 mg/mL to about 5 mg/mL.

A pharmaceutical agent that is disclosed herein can be made more solublein a formulation by the addition of an additive or agent. Theimprovement of solubility of the formulation can increase by about 5%,about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%,about 75% about 80%, about 85%, about 90%, about 95%, about 100%, about110%, about 120%, about 130%, about 140%, about 150%, about 160%, about170%, about 180%, about 190%, about 200%, about 225%, about 250%, about275%, about 300%, about 325%, about 350%, about 375%, about 400%, about450%, or about 500%.

A first compound, for example, pregabalin, of a pharmaceuticalformulation described herein can be made more soluble by the addition ofa second compound, for example, acetaminophen, described herein. Thesolubility of the first or second compound can increase by about 5%,about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%,about 75% about 80%, about 85%, about 90%, about 95%, about 100%, about110%, about 120%, about 130%, about 140%, about 150%, about 160%, about170%, about 180%, about 190%, about 200%, about 225%, about 250%, about275%, about 300%, about 325%, about 350%, about 375%, about 400%, about450%, or about 500% in the presence of the other compound.

The stability of a pharmaceutical formulation described herein can bedetermined by analyzing the amount of active ingredient remaining over aspecific time period at a specific temperature when formulated, forexample, at a specific pH. Additionally, the stability of thepharmaceutical formulation can be assessed by determining the amount ofimpurities present in the pharmaceutical formulation over a specifictime period at a specific temperature when formulated, for example, at aspecific pH. The amount of active ingredient and impurities can bedetermined by, for example, high-performance liquid chromatography(HPLC).

A formulation disclosed herein can be stable for about 1 day, about 2days, about 3 days, about 4 days, about 5 days, about 6 days, about 7days, about 8 days, about 9 days, about 10 days, about 2 weeks, about 4weeks, about 6 weeks, about 8 weeks, about 10 weeks, about 12 weeks,about 3 months, about 4 months, about 5 months, about 6 months, about 7months, about 8 months, about 9 months, about 10 months, about 11months, or about one year. A formulation disclosed herein can be stable,for example, at about 0° C., about 5° C., about 10° C., about 15° C.,about 20° C., about 25° C., about 30° C., about 35° C., about 40° C.,about 45° C., about 50° C., about 60° C., about 70° C., or about 80° C.A formulation described herein can be stable for or be stored for, forexample, about 1 hour, about 2 hours, about 3 hours, about 4 hours,about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours,about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours,about 23 hours, about 24 hours, about 30 hours, about 36 hours, about 42hours, about 48 hours, about 60 hours, about 3 days, about 4 days, about5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks,about 9 weeks, about 10 weeks, about 11 weeks, about 3 months, about 4months, about 5 months, about 6 months, about 7 months, about 8 months,about 9 months, about 10 months, about 11 months, about 1 year, about 13months, about 14 months, about 15 months, about 16 months, about 17months, about 18 months, about 19 months, about 20 months, about 21months, about 22 months, about 23 months, about 2 years, about 25months, about 26 months, about 27 months, about 28 months, about 29months, about 30 months, about 31 months, about 32 months, about 33months, about 34 months, about 35 months, or about 3 years prior toadministration to a subject.

A unit dosage form described herein can be stable for or be stored for,for example, about 1 hour, about 2 hours, about 3 hours, about 4 hours,about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours,about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours,about 23 hours, about 24 hours, about 30 hours, about 36 hours, about 42hours, about 48 hours, about 60 hours, about 3 days, about 4 days, about5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks,about 9 weeks, about 10 weeks, about 11 weeks, about 3 months, about 4months, about 5 months, about 6 months, about 7 months, about 8 months,about 9 months, about 10 months, about 11 months, about 1 year, about 13months, about 14 months, about 15 months, about 16 months, about 17months, about 18 months, about 19 months, about 20 months, about 21months, about 22 months, about 23 months, about 2 years, about 25months, about 26 months, about 27 months, about 28 months, about 29months, about 30 months, about 31 months, about 32 months, about 33months, about 34 months, about 35 months, or about 3 years prior toadministration to a subject.

The stability of a formulation described herein can be measured after,for example, about 1 hour, about 2 hours, about 3 hours, about 4 hours,about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours,about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours,about 23 hours, about 24 hours, about 30 hours, about 36 hours, about 42hours, about 48 hours, about 60 hours, about 3 days, about 4 days, about5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks,about 9 weeks, about 10 weeks, about 11 weeks, about 3 months, about 4months, about 5 months, about 6 months, about 7 months, about 8 months,about 9 months, about 10 months, about 11 months, about 1 year, about 13months, about 14 months, about 15 months, about 16 months, about 17months, about 18 months, about 19 months, about 20 months, about 21months, about 22 months, about 23 months, about 2 years, about 25months, about 26 months, about 27 months, about 28 months, about 29months, about 30 months, about 31 months, about 32 months, about 33months, about 34 months, about 35 months, or about 3 years.

Pharmaceutical compositions described herein can be used, stored,tested, analyzed or assayed at any suitable temperature. Non-limitingexamples of temperatures include about 0° C., about 1° C., about 2° C.,about 3° C., about 4° C., about 5° C., about 6° C., about 7° C., about8° C., about 9° C., about 10° C., about 11° C., about 12° C., about 13°C., about 14° C., about 15° C., about 16° C., about 17° C., about 18°C., about 19° C., about 20° C., about 21° C., about 22° C., about 23°C., about 24° C., about 25° C., about 26° C., about 27° C., about 28°C., about 29° C., about 30° C., about 31° C., about 32° C., about 33°C., about 34° C., about 35° C., about 36° C., about 37° C., about 38°C., about 39° C., about 40° C., about 41° C., about 42° C., about 43°C., about 44° C., about 45° C., about 46° C., about 47° C., about 48°C., about 49° C., about 50° C., about 51° C., about 52° C., about 53°C., about 54° C., about 55° C., about 56° C., about 57° C., about 58°C., about 59° C., about 60° C., about 61° C., about 62° C., about 63°C., about 64° C., about 65° C., about 66° C., about 67° C., about 68°C., about 69° C., about 70° C., about 71° C., about 72° C., about 73°C., about 74° C., or about 75° C.

Pharmaceutical compositions described herein can be used, stored,tested, analyzed or assayed at room temperature. The room temperaturecan be, for example, about 20.0° C., about 20.1° C., about 20.2° C.,about 20.3° C., about 20.4° C., about 20.5° C., about 20.6° C., about20.7° C., about 20.8° C., about 20.9° C., about 21.0° C., about 21.1°C., about 21.2° C., about 21.3° C., about 21.4° C., about 21.5° C.,about 21.6° C., about 21.7° C., about 21.8° C., about 21.9° C., about22.0° C., about 22.1° C., about 22.2° C., about 22.3° C., about 22.4°C., about 22.5° C., about 22.6° C., about 22.7° C., about 22.8° C.,about 22.9° C., about 23.0° C., about 23.1° C., about 23.2° C., about23.3° C., about 23.4° C., about 23.5° C., about 23.6° C., about 23.7°C., about 23.8° C., about 23.9° C., about 24.0° C., about 24.1° C.,about 24.2° C., about 24.3° C., about 24.4° C., about 24.5° C., about24.6° C., about 24.7° C., about 24.8° C., about 24.9° C., or about 25.0°C.

A pharmaceutical composition described herein can be supplied, stored,or delivered in a vial, tube, container, bag, or vessel that is, forexample, about 0.5 mL, about 1 mL, about 2 mL, about 3 mL, about 4 mL,about 5 mL, about 6 mL, about 7 mL, about 8 mL, about 9 mL, about 10 mL,about 11 mL, about 12 mL, about 13 mL, about 14 mL, about 15 mL, about16 mL, about 17 mL, about 18 mL, about 19 mL, about 20 mL, about 25 mL,about 30 mL, about 35 mL, about 40 mL, about 45 mL, about 50 mL, about60 mL, about 70 mL, about 80 mL, about 90 mL, about 100 mL, about 150mL, or about 200 mL in volume.

A pharmaceutical formulation described herein can be disposed in acontainer or vessel, which can be sealed. The container or vessel canmaintain the sterility of, or reduce the likelihood of contamination of,the pharmaceutical formulation. The pharmaceutical formulation describedherein can be disposed in a container or vessel and is formulated as,for example, a single use dosage or a multiple use dosage. The containeror vessel can be, for example, a glass vial, an ampoule, or a plasticflexible container. The plastic flexible container can be made of, forexample, PVC (polyvinyl chloride), or polypropylene. A container can bea prefilled syringe.

A pharmaceutical formulation described herein can be stored as a liquidin an aliquot having a total volume of between about 1 and about 500 mL,between about 1 and about 250 mL, between about 1 and about 200 mL,between about 1 and about 150 mL, between about 1 and about 125 mL,between about 1 and about 120 mL, between about 1 and about 110 mL,between about 1 and about 100 mL, between about 1 and about 90 mL,between about 1 and about 80 mL, between about 1 and about 70 mL,between about 1 and about 60 mL, between about 1 and about 50 mL,between about 1 and about 40 mL, between about 1 and about 30 mL,between about 1 and about 20 mL, between about 1 and about 10 mL, orbetween about 1 and about 5 mL.

Dosage Amounts.

In practicing the methods of treatment or use provided herein,therapeutically-effective amounts of the compounds described herein areadministered in pharmaceutical compositions to a subject having adisease or condition to be treated. A therapeutically-effective amountcan vary widely depending on the severity of the disease, the age andrelative health of the subject, the potency of the compounds used, andother factors. Subjects can be, for example, humans, elderly adults,adults, adolescents, pre-adolescents, children, toddlers, infants, orneonates. A subject can be a patient.

Pharmaceutical compositions described herein can be formulated in anysuitable volume. The formulation volume can be, for example, about 0.1mL, about 0.2 mL, about 0.3 mL, about 0.4 mL, about 0.5 mL, about 0.6mL, about 0.7 mL, about 0.8 mL, about 0.9 mL, about 1 mL, about 1.1 mL,about 1.2 mL, about 1.3 mL, about 1.4 mL, about 1.5 mL, about 1.6 mL,about 1.7 mL, about 1.8 mL, about 1.9 mL, about 2 mL, about 2.1 mL,about 2.2 mL, about 2.3 mL, about 2.4 mL, about 2.5 mL, about 2.6 mL,about 2.7 mL, about 2.8 mL, about 2.9 mL, about 3 mL, about 3.1 mL,about 3.2 mL, about 3.3 mL, about 3.4 mL, about 3.5 mL, about 3.6 mL,about 3.7 mL, about 3.8 mL, about 3.9 mL, about 4 mL, about 4.1 mL,about 4.2 mL, about 4.3 mL, about 4.4 mL, about 4.5 mL, about 4.6 mL,about 4.7 mL, about 4.8 mL, about 4.9 mL, about 5 mL, about 5.1 mL,about 5.2 mL, about 5.3 mL, about 5.4 mL, about 5.5 mL, about 5.6 mL,about 5.7 mL, about 5.8 mL, about 5.9 mL, about 6 mL, about 6.1 mL,about 6.2 mL, about 6.3 mL, about 6.4 mL, about 6.5 mL, about 6.6 mL,about 6.7 mL, about 6.8 mL, about 6.9 mL, about 7 mL, about 7.1 mL,about 7.2 mL, about 7.3 mL, about 7.4 mL, about 7.5 mL, about 7.6 mL,about 7.7 mL, about 7.8 mL, about 7.9 mL, about 8 mL, about 8.1 mL,about 8.2 mL, about 8.3 mL, about 8.4 mL, about 8.5 mL, about 8.6 mL,about 8.7 mL, about 8.8 mL, about 8.9 mL, about 9 mL, about 9.1 mL,about 9.2 mL, about 9.3 mL, about 9.4 mL, about 9.5 mL, about 9.6 mL,about 9.7 mL, about 9.8 mL, about 9.9 mL, about 10 mL, about 11 mL,about 12 mL, about 13 mL, about 14 mL, about 15 mL, about 16 mL, about17 mL, about 18 mL, about 19 mL, about 20 mL, about 30 mL, about 40 mL,about 50 mL, about 60 mL, about 70 mL, about 80 mL, about 90 mL, about100 mL, about 150 mL, or about 200 mL. The formulation volume can be,for example, about 0.1 mL to about 200 mL, about 0.1 mL to about 100 mL,about 0.1 mL to about 50 mL, about 0.1 mL to about 25 mL, about 0.1 mLto about 20 mL, about 0.1 mL to about 15 mL, about 0.1 mL to about 10mL, about 0.1 mL to about 5 mL, about 0.1 mL to about 3 mL, about 0.1 mLto about 2 mL, about 0.1 mL to about 1 mL, about 1 mL to about 10 mL,about 1 mL to about 5 mL, about 1 mL to about 3 mL, or about 1 mL toabout 2 mL.

A therapeutically-effective amount of a compound described herein can bepresent in a composition described herein at a mass of, for example,about 0.01 μg, about 0.05 μg, about 0.1 μg, about 0.15 μg, about 0.2 μg,about 0.25 μg, about 0.3 μg, about 0.35 μg, about 0.4 μg, about 0.5 μg,about 0.6 μg, about 0.7 μg, about 0.8 μg, about 0.9 μg, about 1 μg,about 2 μg, about 3 μg, about 4 μg, about 5 μg, about 10 μg, about 15μg, about 20 μg, about 25 μg, about 30 μg, about 35 μg, about 40 μg,about 45 μg, about 50 μg, about 60 μg, about 70 μg, about 80 μg, about90 μg, about 100 μg, about 125 μg, about 150 μg, about 175 μg, about 200μg, about 250 μg, about 300 μg, about 350 μg, about 400 μg, about 450μg, about 500 μg, about 600 μg, about 700 μg, about 800 μg, about 900μg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg,about 18 mg, about 19 mg, or about 20 mg. A therapeutically-effectiveamount of a compound described herein can be present in a compositiondescribed herein at a mass of, for example, about 0.01 μg to about 20mg, about 0.01 μg to about 1 mg, about 0.01 μg to about 100 μg, about0.01 μg to about 10 μg, about 0.1 μg to about 10 μg, about 1 μg to about10 μg, about 500 μg, to about 1 mg, about 1 mg to about 20 mg, about 1mg to about 10 mg, about 1 mg to about 5 mg, about 1 mg to about 2 mg,about 5 mg to about 20 mg, or about 10 mg to about 20 mg.

A therapeutically-effective amount of a compound described herein can bepresent in a composition described herein at a concentration of, forexample, about 0.001 mg/mL, about 0.002 mg/mL, about 0.003 mg/mL, about0.004 mg/mL, about 0.005 mg/mL, about 0.006 mg/mL, about 0.007 mg/mL,about 0.008 mg/mL, about 0.009 mg/mL, about 0.01 mg/mL, about 0.02mg/mL, about 0.03 mg/mL, about 0.04 mg/mL, about 0.05 mg/mL, about 0.06mg/mL, about 0.07 mg/mL, about 0.08 mg/mL, about 0.09 mg/mL, about 0.1mg/mL, about 0.2 mg/mL, about 0.25 mg/mL, about 0.3 mg/mL, about 0.4mg/mL, about 0.5 mg/mL, about 0.6 mg/mL, about 0.7 mg/mL, about 0.8mg/mL, about 0.9 mg/mL, about 1 mg/mL, about 1.5 mg/mL, about 2 mg/mL,about 2.5 mg/mL, about 3 mg/mL, about 3.5 mg/mL, about 4 mg/mL, about4.5 mg/mL, about 5 mg/mL, about 6 mg/mL, about 7 mg/mL, about 8 mg/mL,about 9 mg/mL, about 10 mg/mL, about 15 mg/mL, about 20 mg/mL, about 25mg/mL, about 30 mg/mL, about 35 mg/mL, about 40 mg/mL, about 45 mg/mL,about 50 mg/mL, about 60 mg/mL, about 70 mg/mL, about 80 mg/mL, about 90mg/mL, or about 100 mg/mL. A therapeutically-effective amount of acompound described herein can be present in a composition describedherein at a concentration of, for example, from about 0.1 mg/mL to about20 mg/mL, from about 0.1 mg/mL to about 50 mg/mL, from about 0.25 mg/mLto about 6 mg/mL, from about 1 mg/mL to about 20 mg/mL, from about 2mg/mL to about 20 mg/mL, from about 5 mg/mL to about 15 mg/mL, fromabout 8 mg/mL to about 12 mg/mL, from about 9 mg/mL to about 11 mg/mL,from about 9.5 mg/mL to about 10.5 mg/mL, from about 9.9 mg/mL to about10.1 mg/mL, from about 3 mg/mL to about 6 mg/mL, from about 3.5 mg/mL toabout 5.5 mg/mL, from about 4 mg/mL to about 5 mg/mL, or from about 4.4mg/mL to about 4.6 mg/mL. A therapeutically-effective amount of acompound described herein can be present in a composition describedherein at a concentration of, for example, at least about 0.5 mg/mL, atleast about 1 mg/mL, at least about 1.5 mg/mL, at least about 3 mg/mL,or at least about 5 mg/mL. In the same formulation, thetherapeutically-effective amount of acetaminophen can be at least about8 mg/mL, at least about 10 mg/mL, at least about 15 mg/mL, or at leastabout 20 mg/mL.

A therapeutically-effective amount of a compound described herein can bea dose based on the body mass of the subject, for example, about 0.5mg/kg, about 1 mg/kg, about 1.25 mg/kg, about 1.5 mg/kg, about 1.75mg/kg, about 2 mg/kg, about 2.25 mg/kg, about 2.5 mg/kg, about 2.75mg/kg, about 3 mg/kg, about 3.25 mg/kg, about 3.5 mg/kg, about 3.75mg/kg, about 4 mg/kg, about 4.25 mg/kg, about 4.5 mg/kg, about 4.75mg/kg, about 5 mg/kg, about 5.25 mg/kg, about 5.5 mg/kg, about 5.75mg/kg, about 6 mg/kg, about 6.25 mg/kg, about 6.5 mg/kg, about 6.75mg/kg, about 7 mg/kg, about 7.25 mg/kg, about 7.5 mg/kg, about 7.75mg/kg, about 8 mg/kg, about 8.25 mg/kg, about 8.5 mg/kg, about 8.75mg/kg, about 9 mg/kg, about 9.25 mg/kg, about 9.5 mg/kg, about 9.75mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 13 mg/kg,about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18mg/kg, about 19 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg,about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, or about 50 mg/kg. Atherapeutically-effective amount of a compound described herein can be adose based on the body mass of the subject, for example, about 0.5 mg/kgto about 50 mg/kg, about 0.5 mg/kg to about 1 mg/kg, about 1 mg/kg toabout 5 mg/kg, about 5 mg/kg to about 10 mg/kg, about 10 mg/kg to about15 mg/kg, about 15 mg/kg to about 20 mg/kg, about 20 mg/kg to about 25mg/kg, about 25 mg/kg to about 30 mg/kg, about 30 mg/kg to about 35mg/kg, about 35 mg/kg to about 40 mg/kg, about 40 mg/kg to about 45mg/kg, or about 45 mg/kg to about 50 mg/kg.

Pharmaceutical compositions described herein can be formulated at anysuitable pH. The pH can be, for example, about 2, about 2.05, about 2.1,about 2.15, about 2.2, about 2.25, about 2.3, about 2.35, about 2.4,about 2.45, about 2.5, about 2.55, about 2.6, about 2.65, about 2.7,about 2.75, about 2.8, about 2.85, about 2.9, about 2.95, about 3, about3.05, about 3.1, about 3.15, about 3.2, about 3.25, about 3.3, about3.35, about 3.4, about 3.45, about 3.5, about 3.55, about 3.6, about3.65, about 3.7, about 3.75, about 3.8, about 3.85, about 3.9, about3.95, about 4, about 4.05, about 4.1, about 4.15, about 4.2, about 4.25,about 4.3, about 4.35, about 4.4, about 4.45, about 4.5, about 4.55,about 4.6, about 4.65, about 4.7, about 4.75, about 4.8, about 4.85,about 4.9, about 4.95, about 5, about 5.05, about 5.1, about 5.15, about5.2, about 5.25, about 5.3, about 5.35, about 5.4, about 5.45, about5.5, about 5.55, about 5.6, about 5.65, about 5.7, about 5.75, about5.8, about 5.85, about 5.9, about 5.95, about 6, about 6.05, about 6.1,about 6.15, about 6.2, about 6.25, about 6.3, about 6.35, about 6.4,about 6.45, about 6.5, about 6.55, about 6.6, about 6.65, about 6.7,about 6.75, about 6.8, about 6.85, about 6.9, about 6.95, about 7, about7.05, about 7.1, about 7.15, about 7.2, about 7.25, about 7.3, about7.35, about 7.4, about 7.45, about 7.5, about 7.55, about 7.6, about7.65, about 7.7, about 7.75, about 7.8, about 7.85, about 7.9, about7.95, or about 8.

Pharmaceutical compositions described herein can be formulated at anysuitable pH. The pH can be, for example, from about 2 to about 2.2,about 2.05 to about 2.25, about 2.1 to about 2.3, about 2.15 to about2.35, about 2.2 to about 2.4, about 2.25 to about 2.45, about 2.3 toabout 2.5, about 2.35 to about 2.55, about 2.4 to about 2.6, about 2.45to about 2.65, about 2.5 to about 2.7, about 2.55 to about 2.75, about2.6 to about 2.8, about 2.65 to about 2.85, about 2.7 to about 2.9,about 2.75 to about 2.95, about 2.8 to about 3, about 2.85 to about3.05, about 2.9 to about 3.1, about 2.95 to about 3.15, about 3 to about3.2, about 3.05 to about 3.25, about 3.1 to about 3.3, about 3.15 toabout 3.35, about 3.2 to about 3.4, about 3.25 to about 3.45, about 3.3to about 3.5, about 3.35 to about 3.55, about 3.4 to about 3.6, about3.45 to about 3.65, about 3.5 to about 3.7, about 3.55 to about 3.75,about 3.6 to about 3.8, about 3.65 to about 3.85, about 3.7 to about3.9, about 3.7 to about 3.8, about 3.75 to about 3.95, about 3.75 toabout 3.8, about 3.8 to about 3.85, about 3.75 to about 3.85, about 3.8to about 4, about 3.85 to about 4.05, about 3.9 to about 4.1, about 3.95to about 4.15, about 4 to about 4.2, about 4.05 to about 4.25, about 4.1to about 4.3, about 4.15 to about 4.35, about 4.2 to about 4.4, about4.25 to about 4.45, about 4.3 to about 4.5, about 4.35 to about 4.55,about 4.4 to about 4.6, about 4.45 to about 4.65, about 4.5 to about4.7, about 4.55 to about 4.75, about 4.6 to about 4.8, about 4.65 toabout 4.85, about 4.7 to about 4.9, about 4.75 to about 4.95, about 4.8to about 5, about 4.85 to about 5.05, about 4.9 to about 5.1, about 4.95to about 5.15, about 5 to about 5.2, about 5.05 to about 5.25, about 5.1to about 5.3, about 5.15 to about 5.35, about 5.2 to about 5.4, about5.25 to about 5.45, about 5.3 to about 5.5, about 5.35 to about 5.55,about 5.4 to about 5.6, about 5.45 to about 5.65, about 5.5 to about5.7, about 5.55 to about 5.75, about 5.6 to about 5.8, about 5.65 toabout 5.85, about 5.7 to about 5.9, about 5.75 to about 5.95, about 5.8to about 6, about 5.85 to about 6.05, about 5.9 to about 6.1, about 5.95to about 6.15, about 6 to about 6.2, about 6.05 to about 6.25, about 6.1to about 6.3, about 6.1 to about 6.3, about 6.15 to about 6.35, about6.2 to about 6.4, about 6.25 to about 6.45, about 6.3 to about 6.5,about 6.35 to about 6.55, about 6.4 to about 6.6, about 6.45 to about6.65, about 6.5 to about 6.7, about 6.55 to about 6.85, about 6.6 toabout 6.8, about 6.65 to about 6.85, about 6.7 to about 6.9, about 6.75to about 6.95, about 6.8 to about 7, about 6.85 to about 7.05, about 6.9to about 7.1, about 6.95 to about 7.15, about 7 to about 7.2, about 7.05to about 7.25, about 7.1 to about 7.3, about 7.15 to about 7.35, about7.2 to about 7.4, about 7.25 to about 7.45, about 7.3 to about 7.5,about 7.35 to about 7.55, about 7.4 to about 7.6, about 7.45 to about7.65, about 7.5 to about 7.7, about 7.55 to about 7.75, about 7.6 toabout 7.8, about 7.65 to about 7.85, about 7.7 to about 7.9, about 7.75to about 7.95, about 7.8 to about 8, or about 7.85 to about 8.

In some embodiments, the pH of a pharmaceutical formulation describedherein is about 4 to about 7. In some embodiments, the pH of apharmaceutical formulation described herein is about 4 to about 6. Insome embodiments, the pH of a pharmaceutical formulation describedherein is about 5 to about 6. In some embodiments, the pH of apharmaceutical formulation described herein is about 5.5 to about 6. Insome embodiments, the pH of a pharmaceutical formulation describedherein is 5.5. In some embodiments, the pH of a pharmaceuticalformulation described herein is 6.

A pharmaceutical composition of the disclosure can be a combination ofany pharmaceutical compounds described herein with other chemicalcomponents, such as carriers, stabilizers, diluents, dispersing agents,suspending agents, thickening agents, and/or excipients. Thepharmaceutical composition facilitates administration of the compound toan organism. Pharmaceutical compositions can be administered bytherapeutically-effective routes, for example, oral, intravenous,subcutaneous, intramuscular, subdermal, transdermal, or parenteraladministration. A pharmaceutical formulation described herein can beadministered as an intravenous infusion.

Pharmaceutical preparations can be formulated for intravenousadministration as injectable formulations. The pharmaceuticalformulations can be in a form suitable for parenteral injection as asterile suspension, solution, or emulsion in oily or aqueous vehicles,and can contain formulation agents such as suspending, stabilizing,and/or dispersing agents. Pharmaceutical formulations for parenteraladministration include aqueous solutions of the active compounds inwater-soluble form. Suspensions of the active compounds can be preparedas oily injection suspensions. Suitable lipophilic solvents or vehiclesinclude fatty oils such as sesame oil, or synthetic fatty acid esters,such as ethyl oleate or triglycerides, or liposomes. Aqueous injectionsuspensions can contain substances which increase the viscosity of thesuspension, such as sodium carboxymethyl cellulose, sorbitol, ordextran. The suspension can also contain suitable stabilizers or agentswhich increase the solubility of the compounds to allow for thepreparation of highly concentrated solutions. Alternatively, the activeingredient can be in powder form for constitution with a suitablevehicle, for example, sterile pyrogen-free water, before use.

Compositions described herein can be packaged as a kit. In someembodiments, a kit includes written instructions on the administrationor use of the composition. The written material can be, for example, alabel. The written material can suggest conditions methods ofadministration. The instructions provide the subject and the supervisingphysician with the best guidance for achieving the optimal clinicaloutcome from the administration of the therapy. In some embodiments, thelabel can be approved by a regulatory agency, for example the U.S. Foodand Drug Administration (FDA), the European Medicines Agency (EMA), orother regulatory agencies.

A method of manufacture for a pharmaceutical composition describedherein can involve manufacturing in a manufacturing tank. Themanufacturing tank can contain water that has been, for example,deoxygenated. The deoxygenation of the water in the manufacturing tankcan occur, via, for example, sparging using nitrogen, argon, or helium.The sparging can reduce the amount of oxygen in the water to about 0.01ppm, about 0.02 ppm, about 0.03 ppm, about 0.04 ppm, about 0.05 ppm,about 0.1 ppm, about 0.15 ppm, about 0.2 ppm, about 0.25 ppm, about 0.3ppm, about 0.35 ppm, about 0.4 ppm, about 0.45 ppm, about 0.5 ppm, about0.6 ppm, about 0.7 ppm, about 0.8 ppm, about 0.9 ppm, about 1 ppm, about1.5 ppm, or about 2 ppm.

Pharmaceutically-Acceptable Excipients.

Non-limiting examples of pharmaceutically-acceptable excipients can befound, for example, in Remington: The Science and Practice of Pharmacy,Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, JohnE., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton,Pa. 1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical DosageForms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical DosageForms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams &Wilkins 1999), each of which is incorporated by reference in itsentirety.

In some embodiments, the pharmaceutical composition provided hereincomprises a buffer as an excipient. Non-limiting examples of buffersinclude potassium phosphate, sodium phosphate, phosphate buffer, citratebuffer, saline sodium citrate buffer (SSC), acetate, saline,physiological saline, phosphate buffer saline (PBS),4-2-hydroxyethyl-1-piperazineethanesulfonic acid buffer (HEPES),3-(N-morpholino)propanesulfonic acid buffer (MOPS), andpiperazine-N,N′-bis(2-ethanesulfonic acid) buffer (PIPES), citric acidmonohydrate, sodium dihydrogen phosphate, potassium dihydrogenphosphate, or any combination thereof.

In some embodiments, the pharmaceutical composition provided hereincomprises an alcohol as an excipient. Non-limiting examples of alcoholsinclude ethanol, propylene glycol, glycerol, polyethylene glycol,chlorobutanol, isopropanol, xylitol, sorbitol, maltitol, erythritol,threitol, arabitol, ribitol, mannitol, galactilol, fucitol, lactitol, orany combination thereof.

Pharmaceutical preparations can be formulated with polyethylene glycol(PEG). PEGs with molecular weights ranging from about 300 g/mol to about10,000,000 g/mol can be used. Non-limiting examples of PEGs include PEG200, PEG 300, PEG 400, PEG 540, PEG 550, PEG 600, PEG 1000, PEG 1450,PEG 1500, PEG 2000, PEG 3000, PEG 3350, PEG 4000, PEG 4600, PEG 6000,PEG 8000, PEG 10,000, and PEG 20,000.

Further excipients that can be used in a composition described hereininclude, for example, benzalkonium chloride, benzethonium chloride,benzyl alcohol, butylated hydroxyanisole, butylated hydroxytoluene,chlorobutanol, dehydroacetic acid, ethylenediamine, ethyl vanillin,glycerin, hypophosphorous acid, phenol, phenylethyl alcohol,phenylmercuric nitrate, potassium benzoate, potassium metabisulfite,potassium sorbate, sodium bisulfite, sodium metabisulfite, sorbic acid,thimerasol, acetic acid, aluminum monostearate, boric acid, calciumhydroxide, calcium stearate, calcium sulfate, calcium tetrachloride,cellulose acetate pthalate, microcrystalline celluose, chloroform,citric acid, edetic acid, and ethylcellulose.

In some embodiments, the pharmaceutical composition provided hereincomprises an aprotic solvent as an excipient. Non-limiting examples ofaprotic solvents include perfluorohexane, α,α,α-trifluorotoluene,pentane, hexane, cyclohexane, methylcyclohexane, decalin, dioxane,carbon tetrachloride, freon-11, benzene, toluene, carbon disulfide,diisopropyl ether, diethyl ether, t-butyl methyl ether, ethyl acetate,1,2-dimethoxyethane, 2-methoxyethyl ether, tetrahydrofuran, methylenechloride, pyridine, 2-butanone, acetone, N-methylpyrrolidinone,nitromethane, dimethylformamide, acetonitrile, sulfolane, dimethylsulfoxide, and propylene carbonate.

The amount of the excipient in a pharmaceutical composition describedherein can be about 0.01%, about 0.02%, about 0.03%, about 0.04%, about0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%,about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%,about 0.8%, about 0.9%, about 1%, about 1.5%, about 2%, about 2.5%,about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 6%, about7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%,about 30%, about 35%, about 40%, about 45%, about 50%, about 60%, about70%, about 80%, about 90%, about 100%, about 200%, about 300%, about400%, about 500%, about 600%, about 700%, about 800%, about 900%, orabout 1000% by mass of a compound in the pharmaceutical formulation.

The amount of the excipient in a pharmaceutical composition describedherein can be about 0.01%, about 0.02%, about 0.03%, about 0.04%, about0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%,about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%,about 0.8%, about 0.9%, about 1%, about 1.5%, about 2%, about 2.5%,about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 6%, about7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%,about 30%, about 35%, about 40%, about 45%, about 50%, about 55% about60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%,about 95%, about 99%, or about 100% by mass or by volume of the unitdosage form.

In some embodiments, the addition of an excipient can change theviscosity of a pharmaceutical composition described herein. In someembodiments the use of an excipient can increase or decrease theviscosity of a fluid by at least 0.001 Pascal-second (Pa.$), at least0.001 Pa·s, at least 0.0009 Pa·s, at least 0.0008 Pa·s, at least 0.0007Pa·s, at least 0.0006 Pa·s, at least 0.0005 Pa·s, at least 0.0004 Pa·s,at least 0.0003 Pa·s, at least 0.0002 Pa·s, at least 0.0001 Pa·s, atleast 0.00005 Pa·s, or at least 0.00001 Pa·s.

In some embodiments, the addition of an excipient to a pharmaceuticalcomposition described herein can increase or decrease the viscosity ofthe composition by at least 5%, at least 10%, at least 15%, at least20%, at least 25%, at least 30%, at least 35%, at least 40%, at least45%, at least 50%, at least 55%, at least 60%, at least 65%, at least70%, at least 75%, at least 80%, at least 85%, at least 90%, at least95%, or at least 99%. In some embodiments, the addition of an excipientto a pharmaceutical composition described herein can increase ordecrease the viscosity of the composition by no greater than 5%, nogreater than 10%, no greater than 15%, no greater than 20%, no greaterthan 25%, no greater than 30%, no greater than 35%, no greater than 40%,no greater than 45%, no greater than 50%, no greater than 55%, nogreater than 60%, no greater than 65%, no greater than 70%, no greaterthan 75%, no greater than 80%, no greater than 85%, no greater than 90%,no greater than 95%, or no greater than 99%.

Purity.

A formulation or unit dosage form described herein can exhibit, forexample, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%,about 0.6%, about 0.7%, about 0.8%, about 0.9% about 1%, about 1.1%,about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%,about 1.8%, about 1.9%, about 2%, about 2.1%, about 2.2%, about 2.3%,about 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9%,about 3%, about 3.1%, about 3.2%, about 3.3%, about 3.4%, about 3.5%,about 3.6%, about 3.7%, about 3.8%, about 3.9%, about 4%, about 4.1%,about 4.2%, about 4.3%, about 4.4%, about 4.5%, about 4.6%, about 4.7%,about 4.8%, about 4.9%, about 5%, about 5.5%, about 6%, about 6.5%,about 7%, about 7.5%, about 8%, about 8.5%, about 9%, about 9.5%, orabout 10% degradation over a specified period of time. The degradationof a formulation or a unit dosage form disclosed herein can be assessedafter about 24 hours, about 36 hours, about 72 hours, about 96 hours,about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5weeks, about 6 weeks, about 2 months, about 3 months, about 4 months,about 5 months, about 6 months, about 8 months, about 10 months, about 1year, about 13 months, about 14 months, about 15 months, about 16months, about 17 months, about 18 months, about 19 months, about 20months, about 21 months, about 22 months, about 23 months, about 2years, about 25 months, about 26 months, about 27 months, about 28months, about 29 months, about 30 months, about 31 months, about 32months, about 33 months, about 34 months, about 35 months, or about 3years of storage. The degradation of a formulation or a unit dosage formdisclosed herein can be assessed at a temperature of, for example, about0° C., about 1° C., about 2° C., about 3° C., about 4° C., about 5° C.,about 6° C., about 7° C., about 8° C., about 9° C., about 10° C., about11° C., about 12° C., about 13° C., about 14° C., about 15° C., about16° C., about 17° C., about 18° C., about 19° C., about 20° C., about21° C., about 22° C., about 23° C., about 24° C., about 25° C., about26° C., about 27° C., about 28° C., about 29° C., about 30° C., about31° C., about 32° C., about 33° C., about 34° C., about 35° C., about36° C., about 37° C., about 38° C., about 39° C., about 40° C., about41° C., about 42° C., about 43° C., about 44° C., about 45° C., about46° C., about 47° C., about 48° C., about 49° C., about 50° C., about55° C., about 60° C., or about 0° C. to about 5° C., about 1° C. toabout 6° C., about 2° C. to about 7° C., about 2° C. to about 8° C.,about 3° C. to about 8° C., about 4° C. to about 9° C., about 5° C. toabout 10° C., about 6° C. to about 11° C., about 7° C. to about 12° C.,about 8° C. to about 13° C., about 9° C. to about 14° C., about 10° C.to about 15° C., about 11° C. to about 16° C., about 12° C. to about 17°C., about 13° C. to about 18° C., about 14° C. to about 19° C., about15° C. to about 20° C., about 16° C. to about 21° C., about 17° C. toabout 22° C., about 18° C. to about 23° C., about 19° C. to about 24°C., about 20° C. to about 25° C., about 21° C. to about 26° C., about22° C. to about 27° C., about 23° C. to about 28° C., about 24° C. toabout 29° C., about 25° C. to about 30° C., about 26° C. to about 31°C., about 27° C. to about 32° C., about 28° C. to about 33° C., about29° C. to about 34° C., about 30° C. to about 35° C., about 31° C. toabout 36° C., about 32° C. to about 37° C., about 33° C. to about 38°C., about 34° C. to about 39° C., about 35° C. to about 40° C., about36° C. to about 41° C., about 37° C. to about 42° C., about 38° C. toabout 43° C., about 39° C. to about 44° C., about 40° C. to about 45°C., about 41° C. to about 46° C., about 42° C. to about 47° C., about43° C. to about 48° C., about 44° C. to about 49° C., about 45° C. toabout 50° C., or about 55° C. to about 60° C.

The purity of a pharmaceutical formulation described herein can bedetermined by analyzing the amount of active ingredient remaining over aspecific time period at a specific temperature, when formulated, forexample, at a specific pH. Additionally, the purity of thepharmaceutical formulation can be assessed by determining the amount ofimpurities present in the pharmaceutical formulation over a specifictime period at a specific temperature, when formulated, for example, ata specific pH. The amount of active ingredient and impurities can bedetermined by, for example, HPLC.

Any compound herein can be purified. A compound can be at least 1% pure,at least 2% pure, at least 3% pure, at least 4% pure, at least 5% pure,at least 6% pure, at least 7% pure, at least 8% pure, at least 9% pure,at least 10% pure, at least 11% pure, at least 12% pure, at least 13%pure, at least 14% pure, at least 15% pure, at least 16% pure, at least17% pure, at least 18% pure, at least 19% pure, at least 20% pure, atleast 21% pure, at least 22% pure, at least 23% pure, at least 24% pure,at least 25% pure, at least 26% pure, at least 27% pure, at least 28%pure, at least 29% pure, at least 30% pure, at least 31% pure, at least32% pure, at least 33% pure, at least 34% pure, at least 35% pure, atleast 36% pure, at least 37% pure, at least 38% pure, at least 39% pure,at least 40% pure, at least 41% pure, at least 42% pure, at least 43%pure, at least 44% pure, at least 45% pure, at least 46% pure, at least47% pure, at least 48% pure, at least 49% pure, at least 50% pure, atleast 51% pure, at least 52% pure, at least 53% pure, at least 54% pure,at least 55% pure, at least 56% pure, at least 57% pure, at least 58%pure, at least 59% pure, at least 60% pure, at least 61% pure, at least62% pure, at least 63% pure, at least 64% pure, at least 65% pure, atleast 66% pure, at least 67% pure, at least 68% pure, at least 69% pure,at least 70% pure, at least 71% pure, at least 72% pure, at least 73%pure, at least 74% pure, at least 75% pure, at least 76% pure, at least77% pure, at least 78% pure, at least 79% pure, at least 80% pure, atleast 81% pure, at least 82% pure, at least 83% pure, at least 84% pure,at least 85% pure, at least 86% pure, at least 87% pure, at least 88%pure, at least 89% pure, at least 90% pure, at least 91% pure, at least92% pure, at least 93% pure, at least 94% pure, at least 95% pure, atleast 96% pure, at least 97% pure, at least 98% pure, at least 99% pure,at least 99.1% pure, at least 99.2% pure, at least 99.3% pure, at least99.4% pure, at least 99.5% pure, at least 99.6% pure, at least 99.7%pure, at least 99.8% pure, or at least 99.9% pure.

The amount of impurity in a composition described herein can be, forexample, about 0.01%, about 0.02%, about 0.03%, about 0.04%, about0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%,about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%,about 0.8%, about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%,about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%,about 2%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%,about 2.6%, about 2.7%, about 2.8%, about 2.9%, about 3%, about 3.1%,about 3.2%, about 3.3%, about 3.4%, about 3.5%, about 3.6%, about 3.7%,about 3.8%, about 3.9%, about 4%, about 4.1%, about 4.2%, about 4.3%,about 4.4%, about 4.5%, about 4.6%, about 4.7%, about 4.8%, about 4.9%,about 5%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%, about8%, about 8.5%, about 9%, about 9.5%, about 10%, about 11%, about 12%,about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about19%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%,about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about80%, about 85%, about 90%, about 95%, or about 100% by mass of acompound present in the composition.

The amount of degradation of one or both of the non-opioid analgesicspresent in a formulation described herein can be maintained to be belowabout 10%, about 5%, or about 2% when the formulation is stored as aliquid formulation for over at least about one week, at least about twoweeks, at least about three weeks, or at least about one month at atemperature of less than about 60° C.

The impurities in a pharmaceutical formulation described herein caninclude, for example, 4-aminophenol (para-aminophenol),4-(2-methylpropyl)pyrrolidin-2-one (MPP; pregabalin lactam), or anyunknown impurity.

Non-limiting examples of methods that can be used to identify impuritiesand the amount of active ingredient in a formulation described hereininclude HPLC, reversed-phase HPLC (RP-HPLC), mass spectrometry (MS),Matrix Assisted Laser Desorption Ionization Time-of-Flight (MALDI-TOF),electrospray ionization Time-of-flight (ESI-TOF), gaschromatography-mass spectrometry (GC-MS), liquid chromatography-massspectrometry (LC-MS), and two-dimensional gel electrophoresis.

HPLC can be used to identify impurities using high pressure to separatecomponents of a mixture through a packed column of solid adsorbentmaterial, denoted the stationary phase. The sample components caninteract differently with the column based upon the pressure applied tothe column, material used in stationary phase, size of particles used inthe stationary phase, the composition of the solvent used in the column,and the temperature of the column. The interaction between the samplecomponents and the stationary phase can affect the time required for acomponent of the sample to move through the column. The time requiredfor component to travel through the column from injection point toelution is known as the retention time.

Upon elution from the column, the eluted component can be detected usinga UV detector attached to the column. The wavelength of light at whichthe component is detected, in combination with the component's retentiontime, can be used to identify the component. Further, the peak displayedby the detector can be used to determine the quantity of the componentpresent in the initial sample. Wavelengths of light that can be used todetect sample components include, for example, about 200 nM, about 225nm, about 250 nm, about 275 nm, about 300 nm, about 325 nm, about 350nm, about 375 nm, and about 400 nm.

Mass spectrometry (MS) can also be used to identify impurities in aformulation described herein. The samples can be injected into a massspectrometer. Upon injection, the sample can be ionized and detected asions on a spectrum according to the mass to charge ratio created uponionization. The mass to charge ratio can then be used to determine theimpurities present in the sample.

Pharmacokinetics and Pharmacodynamics.

A dose can be modulated to achieve a desired pharmacokinetic orpharmacodynamics profile, such as a desired or effective blood profile,as described herein.

Pharmacokinetic and pharmacodynamic data can be obtained by variousexperimental techniques. Appropriate pharmacokinetic and pharmacodynamicprofile components describing a particular composition can vary due tovariations in drug metabolism in human subjects. Pharmacokinetic andpharmacodynamic profiles can be based on the determination of the meanparameters of a group of subjects. The group of subjects includes anyreasonable number of subjects suitable for determining a representativemean, for example, 5 subjects, 10 subjects, 15 subjects, 20 subjects, 25subjects, 30 subjects, 35 subjects, or more. The mean is determined, forexample, by calculating the average of all subject's measurements foreach parameter measured. A dose can be modulated to achieve a desiredpharmacokinetic or pharmacodynamics profile, such as a desired oreffective blood profile, as described herein.

The pharmacodynamic parameters can be any parameters suitable fordescribing compositions described herein. For example, thepharmacodynamic profile can be obtained at a time after dosing of, forexample, about zero minutes, about 1 minute, about 2 minutes, about 3minutes, about 4 minutes, about 5 minutes, about 6 minutes, about 7minutes, about 8 minutes, about 9 minutes, about 10 minutes, about 11minutes, about 12 minutes, about 13 minutes, about 14 minutes, about 15minutes, about 16 minutes, about 17 minutes, about 18 minutes, about 19minutes, about 20 minutes, about 21 minutes, about 22 minutes, about 23minutes, about 24 minutes, about 25 minutes, about 26 minutes, about 27minutes, about 28 minutes, about 29 minutes, about 30 minutes, about 31minutes, about 32 minutes, about 33 minutes, about 34 minutes, about 35minutes, about 36 minutes, about 37 minutes, about 38 minutes, about 39minutes, about 40 minutes, about 41 minutes, about 42 minutes, about 43minutes, about 44 minutes, about 45 minutes, about 46 minutes, about 47minutes, about 48 minutes, about 49 minutes, about 50 minutes, about 51minutes, about 52 minutes, about 53 minutes, about 54 minutes, about 55minutes, about 56 minutes, about 57 minutes, about 58 minutes, about 59minutes, about 60 minutes, about zero hours, about 0.5 hours, about 1hour, about 1.5 hours, about 2 hours, about 2.5 hours, about 3 hours,about 3.5 hours, about 4 hours, about 4.5 hours, about 5 hours, about5.5 hours, about 6 hours, about 6.5 hours, about 7 hours, about 7.5hours, about 8 hours, about 8.5 hours, about 9 hours, about 9.5 hours,about 10 hours, about 10.5 hours, about 11 hours, about 11.5 hours,about 12 hours, about 12.5 hours, about 13 hours, about 13.5 hours,about 14 hours, about 14.5 hours, about 15 hours, about 15.5 hours,about 16 hours, about 16.5 hours, about 17 hours, about 17.5 hours,about 18 hours, about 18.5 hours, about 19 hours, about 19.5 hours,about 20 hours, about 20.5 hours, about 21 hours, about 21.5 hours,about 22 hours, about 22.5 hours, about 23 hours, about 23.5 hours, orabout 24 hours.

The pharmacokinetic parameters can be any parameters suitable fordescribing a compound disclosed herein. The C_(max) can be, for example,not less than about 1 ng/mL; not less than about 5 ng/mL; not less thanabout 10 ng/mL; not less than about 15 ng/mL; not less than about 20ng/mL; not less than about 25 ng/mL; not less than about 50 ng/mL; notless than about 75 ng/mL; not less than about 100 ng/mL; not less thanabout 200 ng/mL; not less than about 300 ng/mL; not less than about 400ng/mL; not less than about 500 ng/mL; not less than about 600 ng/mL; notless than about 700 ng/mL; not less than about 800 ng/mL; not less thanabout 900 ng/mL; not less than about 1000 ng/mL; not less than about1250 ng/mL; not less than about 1500 ng/mL; not less than about 1750ng/mL; not less than about 2000 ng/mL; not less than about 5000 mg/mL;not less than about 10,000 ng/mL; not less than about 15,000 ng/mL; notless than about 20,000 ng/mL; not less than about 30,000 ng/mL; not lessthan about 40,000 n g/mL; or any other C_(max) appropriate fordescribing a pharmacokinetic profile of a compound described herein. TheC_(max) can be, for example, about 1 ng/mL to about 5,000 ng/mL; about 1ng/mL to about 4,500 ng/mL; about 1 ng/mL to about 4,000 ng/mL; about 1ng/mL to about 3,500 ng/mL; about 1 ng/mL to about 3,000 ng/mL; about 1ng/mL to about 2,500 ng/mL; about 1 ng/mL to about 2,000 ng/mL; about 1ng/mL to about 1,500 ng/mL; about 1 ng/mL to about 1,000 ng/mL; about 1ng/mL to about 900 ng/mL; about 1 ng/mL to about 800 ng/mL; about 1ng/mL to about 700 ng/mL; about 1 ng/mL to about 600 ng/mL; about 1ng/mL to about 500 ng/mL; about 1 ng/mL to about 450 ng/mL; about 1ng/mL to about 400 ng/mL; about 1 ng/mL to about 350 ng/mL; about 1ng/mL to about 300 ng/mL; about 1 ng/mL to about 250 ng/mL; about 1ng/mL to about 200 ng/mL; about 1 ng/mL to about 150 ng/mL; about 1ng/mL to about 125 ng/mL; about 1 ng/mL to about 100 ng/mL; about 1ng/mL to about 90 ng/mL; about 1 ng/mL to about 80 ng/mL; about 1 ng/mLto about 70 ng/mL; about 1 ng/mL to about 60 ng/mL; about 1 ng/mL toabout 50 ng/mL; about 1 ng/mL to about 40 ng/mL; about 1 ng/mL to about30 ng/mL; about 1 ng/mL to about 20 ng/mL; about 1 ng/mL to about 10ng/mL; about 1 ng/mL to about 5 ng/mL; about 10 ng/mL to about 4,000ng/mL; about 10 ng/mL to about 3,000 ng/mL; about 10 ng/mL to about2,000 ng/mL; about 10 ng/mL to about 1,500 ng/mL; about 10 ng/mL toabout 1,000 ng/mL; about 10 ng/mL to about 900 ng/mL; about 10 ng/mL toabout 800 ng/mL; about 10 ng/mL to about 700 ng/mL; about 10 ng/mL toabout 600 ng/mL; about 10 ng/mL to about 500 ng/mL; about 10 ng/mL toabout 400 ng/mL; about 10 ng/mL to about 300 ng/mL; about 10 ng/mL toabout 200 ng/mL; about 10 ng/mL to about 100 ng/mL; about 10 ng/mL toabout 50 ng/mL; about 25 ng/mL to about 500 ng/mL; about 25 ng/mL toabout 100 ng/mL; about 50 ng/mL to about 500 ng/mL; about 50 ng/mL toabout 100 ng/mL; about 100 ng/mL to about 500 ng/mL; about 100 ng/mL toabout 400 ng/mL; about 100 ng/mL to about 300 ng/mL; or about 100 ng/mLto about 200 ng/mL.

The T_(max) of a compound described herein can be, for example, notgreater than about 0.5 hours, not greater than about 1 hours, notgreater than about 1.5 hours, not greater than about 2 hours, notgreater than about 2.5 hours, not greater than about 3 hours, notgreater than about 3.5 hours, not greater than about 4 hours, notgreater than about 4.5 hours, not greater than about 5 hours, or anyother T_(max) appropriate for describing a pharmacokinetic profile of acompound described herein. The T_(max) can be, for example, about 0.1hours to about 24 hours; about 0.1 hours to about 0.5 hours; about 0.5hours to about 1 hour; about 1 hour to about 1.5 hours; about 1.5 hoursto about 2 hour; about 2 hours to about 2.5 hours; about 2.5 hours toabout 3 hours; about 3 hours to about 3.5 hours; about 3.5 hours toabout 4 hours; about 4 hours to about 4.5 hours; about 4.5 hours toabout 5 hours; about 5 hours to about 5.5 hours; about 5.5 hours toabout 6 hours; about 6 hours to about 6.5 hours; about 6.5 hours toabout 7 hours; about 7 hours to about 7.5 hours; about 7.5 hours toabout 8 hours; about 8 hours to about 8.5 hours; about 8.5 hours toabout 9 hours; about 9 hours to about 9.5 hours; about 9.5 hours toabout 10 hours; about 10 hours to about 10.5 hours; about 10.5 hours toabout 11 hours; about 11 hours to about 11.5 hours; about 11.5 hours toabout 12 hours; about 12 hours to about 12.5 hours; about 12.5 hours toabout 13 hours; about 13 hours to about 13.5 hours; about 13.5 hours toabout 14 hours; about 14 hours to about 14.5 hours; about 14.5 hours toabout 15 hours; about 15 hours to about 15.5 hours; about 15.5 hours toabout 16 hours; about 16 hours to about 16.5 hours; about 16.5 hours toabout 17 hours; about 17 hours to about 17.5 hours; about 17.5 hours toabout 18 hours; about 18 hours to about 18.5 hours; about 18.5 hours toabout 19 hours; about 19 hours to about 19.5 hours; about 19.5 hours toabout 20 hours; about 20 hours to about 20.5 hours; about 20.5 hours toabout 21 hours; about 21 hours to about 21.5 hours; about 21.5 hours toabout 22 hours; about 22 hours to about 22.5 hours; about 22.5 hours toabout 23 hours; about 23 hours to about 23.5 hours; or about 23.5 hoursto about 24 hours.

The AUC_((0-inf)) or AUC_((last)) of a compound described herein can be,for example, not less than about 1 ng·hr/mL, not less than about 5ng·hr/mL, not less than about 10 ng·hr/mL, not less than about 20ng·hr/mL, not less than about 30 ng·hr/mL, not less than about 40ng·hr/mL, not less than about 50 ng·hr/mL, not less than about 100ng·hr/mL, not less than about 150 ng·hr/mL, not less than about 200ng·hr/mL, not less than about 250 ng·hr/mL, not less than about 300ng·hr/mL, not less than about 350 ng·hr/mL, not less than about 400ng·hr/mL, not less than about 450 ng·hr/mL, not less than about 500ng·hr/mL, not less than about 600 ng·hr/mL, not less than about 700ng·hr/mL, not less than about 800 ng·hr/mL, not less than about 900ng·hr/mL, not less than about 1000 ng·hr/mL, not less than about 1250ng·hr/mL, not less than about 1500 ng·hr/mL, not less than about 1750ng·hr/mL, not less than about 2000 ng·hr/mL, not less than about 2500ng·hr/mL, not less than about 3000 ng·hr/mL, not less than about 3500ng·hr/mL, not less than about 4000 ng·hr/mL, not less than about 5000ng·hr/mL, not less than about 6000 ng·hr/mL, not less than about 7000ng·hr/mL, not less than about 8000 ng·hr/mL, not less than about 9000ng·hr/mL, not less than about 10,000 ng·hr/mL, not less than about15,000 ng·hr/mL, not less than about 20,000 ng·hr/mL, not less thanabout 25,000 ng·hr/mL, not less than about 30,000 ng·hr/mL, not lessthan about 40,000 ng·hr/mL, not less than about 50,000 ng·hr/mL, or anyother AUC_((0-inf)) appropriate for describing a pharmacokinetic profileof a compound described herein. The AUC_((0-inf)) of a compound can be,for example, about 1 ng·hr/mL to about 10,000 ng·hr/mL; about 1 ng·hr/mLto about 10 ng·hr/mL; about 10 ng·hr/mL to about 25 ng·hr/mL; about 25ng·hr/mL to about 50 ng·hr/mL; about 50 ng·hr/mL to about 100 ng·hr/mL;about 100 ng·hr/mL to about 200 ng·hr/mL; about 200 ng·hr/mL to about300 ng·hr/mL; about 300 ng·hr/mL to about 400 ng·hr/mL; about 400ng·hr/mL to about 500 ng·hr/mL; about 500 ng·hr/mL to about 600ng·hr/mL; about 600 ng·hr/mL to about 700 ng·hr/mL; about 700 ng·hr/mLto about 800 ng·hr/mL; about 800 ng·hr/mL to about 900 ng·hr/mL; about900 ng·hr/mL to about 1,000 ng·hr/mL; about 1,000 ng·hr/mL to about1,250 ng·hr/mL; about 1,250 ng·hr/mL to about 1,500 ng·hr/mL; about1,500 ng·hr/mL to about 1,750 ng·hr/mL; about 1,750 ng·hr/mL to about2,000 ng·hr/mL; about 2,000 ng·hr/mL to about 2,500 ng·hr/mL; about2,500 ng·hr/mL to about 3,000 ng·hr/mL; about 3,000 ng·hr/mL to about3,500 ng·hr/mL; about 3,500 ng·hr/mL to about 4,000 ng·hr/mL; about4,000 ng·hr/mL to about 4,500 ng·hr/mL; about 4,500 ng·hr/mL to about5,000 ng·hr/mL; about 5,000 ng·hr/mL to about 5,500 ng·hr/mL; about5,500 ng·hr/mL to about 6,000 ng·hr/mL; about 6,000 ng·hr/mL to about6,500 ng·hr/mL; about 6,500 ng·hr/mL to about 7,000 ng·hr/mL; about7,000 ng·hr/mL to about 7,500 ng·hr/mL; about 7,500 ng·hr/mL to about8,000 ng·hr/mL; about 8,000 ng·hr/mL to about 8,500 ng·hr/mL; about8,500 ng·hr/mL to about 9,000 ng·hr/mL; about 9,000 ng·hr/mL to about9,500 ng·hr/mL; or about 9,500 ng·hr/mL to about 10,000 ng·hr/mL.

The plasma concentration of a compound described herein can be, forexample, not less than about 1 ng/mL, not less than about 5 ng/mL, notless than about 10 ng/mL, not less than about 15 ng/mL, not less thanabout 20 ng/mL, not less than about 25 ng/mL, not less than about 50ng/mL, not less than about 75 ng/mL, not less than about 100 ng/mL, notless than about 150 ng/mL, not less than about 200 ng/mL, not less thanabout 300 ng/mL, not less than about 400 ng/mL, not less than about 500ng/mL, not less than about 600 ng/mL, not less than about 700 ng/mL, notless than about 800 ng/mL, not less than about 900 ng/mL, not less thanabout 1000 ng/mL, not less than about 1200 ng/mL, or any other plasmaconcentration of a compound described herein. The plasma concentrationcan be, for example, about 1 ng/mL to about 2,000 ng/mL; about 1 ng/mLto about 5 ng/mL; about 5 ng/mL to about 10 ng/mL; about 10 ng/mL toabout 25 ng/mL; about 25 ng/mL to about 50 ng/mL; about 50 ng/mL toabout 75 ng/mL; about 75 ng/mL to about 100 ng/mL; about 100 ng/mL toabout 150 ng/mL; about 150 ng/mL to about 200 ng/mL; about 200 ng/mL toabout 250 ng/mL; about 250 ng/mL to about 300 ng/mL; about 300 ng/mL toabout 350 ng/mL; about 350 ng/mL to about 400 ng/mL; about 400 ng/mL toabout 450 ng/mL; about 450 ng/mL to about 500 ng/mL; about 500 ng/mL toabout 600 ng/mL; about 600 ng/mL to about 700 ng/mL; about 700 ng/mL toabout 800 ng/mL; about 800 ng/mL to about 900 ng/mL; about 900 ng/mL toabout 1,000 ng/mL; about 1,000 ng/mL to about 1,100 ng/mL; about 1,100ng/mL to about 1,200 ng/mL; about 1,200 ng/mL to about 1,300 ng/mL;about 1,300 ng/mL to about 1,400 ng/mL; about 1,400 ng/mL to about 1,500ng/mL; about 1,500 ng/mL to about 1,600 ng/mL; about 1,600 ng/mL toabout 1,700 ng/mL; about 1,700 ng/mL to about 1,800 ng/mL; about 1,800ng/mL to about 1,900 ng/mL; or about 1,900 ng/mL to about 2,000 ng/mL.

The pharmacodynamic parameters can be any parameters suitable fordescribing compositions of the disclosure. For example, thepharmacodynamic profile can demonstrate an increased pain tolerance in asubject who has been administered a pharmaceutical formulation describedherein.

Non-limiting examples of pharmacodynamic and pharmacokinetic parametersthat can be calculated for a compound that is administered with themethods described herein include: a) the amount of drug administered,which can be represented as a dose D; b) the dosing interval, which canbe represented as τ; c) the apparent volume in which a drug isdistributed, which can be represented as a volume of distribution V_(d),where V_(d)=D/C₀; d) the amount of drug in a given volume of plasma,which can be represented as concentration C₀ or C_(ss), where C₀ orC_(ss)=D/V_(d) and can be represented as a mean plasma concentrationover a plurality of samples; e) the half-life of a drug t_(1/2), wheret_(1/2)=ln(2)/k_(e); f) the rate at which a drug is removed from thebody k_(e), where k_(e)=ln(2)/t_(1/2)=CL/V_(d); g) the rate of infusionrequired to balance the equation K_(in), where K_(in)=C_(ss)·CL; h) theintegral of the concentration-time curve after administration of asingle dose, which can be represented as AUC_(0-∞), wherein ∫₀ ^(∞) Cdt, or in steady-state, which can be represented as AUCτ, _(ss), wherein∫_(t) ^(t+π)C dt; i) the volume of plasma cleared of the drug per unittime, which can be represented as CL (clearance), whereinCL=V_(d)·k_(e)=D/AUC; j) the systemically available fraction of a drug,which can be represented as f, where

${f = \frac{{AUCpo}.{Div}}{{AUCiv}.{Dpo}}};$

k) the peak plasma concentration of a drug after administration C_(max);l) the time taken by a drug to reach C_(max), t_(max); m) the lowestconcentration that a drug reaches before the next dose is administeredC_(min); and n) the peak trough fluctuation within one dosing intervalat steady state, which can be represented as % PTF=100.

${\frac{( {{C\max},{{ss} - {C\min}},{ss}} )}{{Cav},{ss}}{where}{}C_{{av},{ss}}} = {\frac{{{AUC}\tau},{ss}}{\tau}.}$

When administered via intravenous injection, a pharmaceuticalcomposition described herein can exert an effect at a level of at leastabout 50%, at least about 70%, at least about 80%, or at least about 90%within less than about, for example, one hour or two hours of theadministration. A pharmaceutical composition described herein can remaineffective at a level of at least about 50%, at least about 70%, at leastabout 80%, or at least about 90% for at least about 1 hour, at leastabout 2 hours, at least about 3 hours, or at least about 6 hours afterthe administration.

A pharmaceutical formulation described herein can be administered to asubject about 1 minute, about 2 minutes, about 3 minutes, about 4minutes, about 5 minutes, about 6 minutes, about 7 minutes, about 8minutes, about 9 minutes, about 10 minutes, about 11 minutes, about 12minutes, about 13 minutes, about 14 minutes, about 15 minutes, about 16minutes, about 17 minutes, about 18 minutes, about 19 minutes, about 20minutes, about 25 minutes, about 30 minutes, about 35 minutes, about 40minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 1hour, about 1.5 hours, about 2 hours, about 2.5 hours, about 3 hours,about 3.5 hours, about 4 hours, about 4.5 hours, about 5 hours, about5.5 hours, about 6 hours, about 6.5 hours, about 7 hours, about 7.5hours, about 8 hours, about 8.5 hours, about 9 hours, about 9.5 hours,about 10 hours, about 10.5 hours, about 11 hours, about 11.5 hours,about 12 hours, about 18 hours, about 24 hours, about 30 hours, about 36hours, about 42 hours, or about 48 hours prior to, or after, surgery. Apharmaceutical formulation described herein can be administered to apatient at the same time as when the surgery begins. A pharmaceuticalformulation described herein can be administered to a patient during asurgery. A pharmaceutical formulation described herein can beadministered to a patient right after a surgery is ended. Apharmaceutical formulation described herein can be administered one ormore times prior to, during, or after, surgery for a patient. Forexample, a pharmaceutical formulation described herein can beadministered to a patient one time a day, two times a day, three times aday, four times a day, five times a day, six times a day, seven times aday, eight times a day, nine times a day, or ten times a day. Apharmaceutical formulation described herein can be administered to apatient every 1 hours, every 2 hours, every 3 hours, every 4 hours,every 5 hours, every 6 hours, every 7 hours, every 8 hours, every 9hours, every 10 hours, every 11 hours, or every 12 hours.

The present disclosure provides several embodiments of pharmaceuticalformulations that provide advantages in stability, administration,efficacy, and modulation of formulation viscosity. Any embodimentsdisclosed herein can be used in conjunction or individually. Forexample, any pharmaceutically-acceptable excipient, method, technique,solvent, or compound disclosed herein can be used together with anyother pharmaceutically-acceptable excipient, method, technique, solvent,or compound disclosed herein to achieve any therapeutic result.Compounds, excipients, and other formulation components can be presentat any amount, ratio, or percentage disclosed herein in any suchformulation, and any such combination can be used therapeutically forany purpose described herein and to provide any viscosity describedherein.

Experimental Methods Used Herein.

Rotarod/Accelerod Test: The rotarod/accelerod test can be used to assessneuromuscular coordination and motor function in rodents. An animal isplaced on an apparatus consisting of a horizontally-oriented circularrod, usually with a ridged surface to enhance grip. The rod is thenrotated about the long axis, with the speed of rotation remainingconstant (rotarod) or increasing over time (accelerod). The animalattempts to remain on the rotating rod, and the latency to fall isrecorded.

The rotarod/accelerod test can be used to screen drugs or drugcombinations for effects on motor function or neuromuscularcoordination. Baseline results can be compared to results aftertreatment, or a control group can be compared to a treatment group.Decreased latency to fall is considered evidence of impairedneuromuscular coordination or motor function, and this can be observedin animal models of neurodegeneration and central nervous system injury.Benzodiazepines such as diazepam can impair performance in therotarod/accelerod test and can serve as positive controls.

Hot Plate Test: The hot plate test is a test that can be used to assesspain sensitivity in rodents. The test is based on the principle thatrodents placed on a hot surface can demonstrate aversion to the noxiousstimulus by paw licking and/or jumping. In the test, an animal is placedin a confined cylindrical space to restrict locomotion. The floorsurface of the space is maintained at a temperature sufficiently hot toelicit an aversive response, but not so hot that tissue damage isinduced, typically 50-56° C. The animal is monitored, and latency to pawlicking or jumping is recorded. This test can be used to screen noveldrugs or drug combinations for effects on pain detection threshold;substances with an analgesic effect can increase latency tolicking/jumping, while substances with a hyperalgesic effect candecrease latency.

In vitro hemolysis test: The in vitro hemolysis test can be used todetermine whether a treatment of interest exhibits erythrocyte (redblood cell)-lysing activity. Drug candidates can be tested to assess thepotential of the active compound, metabolites thereof, or excipients inthe formulation to cause toxic hemolysis, which in vivo can result inneutropenia, thrombocytopenia, hemolytic anemia, aplastic anemia, ormacrocytic anemia.

The compound of interest is serially-diluted and applied to erythrocytessuspended in either plasma or isotonic buffer. As a positive control,erythrocytes are treated with a known hemolytic agent (for example,sodium dodecyl sulfate), and as a negative control erythrocytes aretreated with a vehicle lacking the test compound (for example, dimethylsulfoxide). The samples are then incubated at 37° C., centrifuged toremove intact cells and large particulate matter, and the supernatantabsorbance measured via spectrophotometry. The absorbance can increaseproportionally with hemolysis due to the presence of hemoglobin in thesupernatant. Percent hemolysis in each sample can then be calculatedusing a formula similar to:

${{percent}{hemolysis}} = {100 \times {\frac{( {{{absorbance}{of}{sample}} - {{absorbance}{of}{negative}{control}}} )}{( {{{absorbance}{of}{positive}{control}} - {{absorbance}{of}{negative}{control}}} )}.}}$

EXAMPLES Example 1: The Effect of pH on the Solubility of Pregabalin andAcetaminophen

The solubility of pregabalin (PGB) and acetaminophen (APAP) wasdetermined at room temperature in water at different pH values. Thesamples were prepared by adding acetaminophen in water at aconcentration of 50 mg/mL, and pregabalin at a concentration of 100mg/mL. The pH was then adjusted to the required range. The concentrationof the active ingredients was determined by HPLC-UV.

As can be seen from TABLE 1, no significant difference in the solubilityof acetaminophen was observed in the pH range from 4-7.

The solubility of pregabalin was higher at pH 4 and was found to beabout 31 mg/mL at the pH range of 5-7, as shown in TABLE 2.

TABLE 1 Sample Acetaminophen (mg/mL) pH 4 13.8 pH 5 13.9 pH 6 13.8 pH 713.9

TABLE 2 Sample Pregabalin (mg/mL) pH 4 54.4 pH 5 32.4 pH 6 31.0 pH 730.6

The concentration of pregabalin and acetaminophen in an aqueous carriercan be increased when the pregabalin and acetaminophen are co-dissolvedin the aqueous carrier. Solubility samples were prepared by addingacetaminophen and pregabalin in water at 50 mg/mL and 100 mg/mLconcentration, respectively, and adjusting the pH to the required range.

As can be seen from TABLE 3, the solubility of acetaminophen wasincreased to about 21 mg/mL in presence of pregabalin, which was morethan 1.5 times the solubility obtained for acetaminophen alone at pH 4.Also, the increase in the solubility of pregabalin in the presence ofacetaminophen was observed within the pH range of 5-7 in comparison tosolubility values obtained in the same DH range for pregabalin alone.

TABLE 3 Sample Acetaminophen (mg/mL) Pregabalin (mg/mL) pH 4 20.8 54.4pH 5 18.7 36.8 pH 6 17.9 35.0 pH 7 17.9 35.0

Example 2: Stability of Acetaminophen and Pregabalin Formulations

To determine the stability of acetaminophen and pregabalinco-formulations, citrate buffer (10 mM), acetate buffer (10 mM), andphosphate buffer (10 mM) were disposed in four separate manufacturingtanks as shown in TABLE 4. Pregabalin, acetaminophen, and otherexcipients were added to each of the tanks, and filled with the requiredquantities of water (water for injection) to obtain a concentration of4.5 and 10 mg/mL, respectively.

Then, the pH of each of the tanks was readjusted using HCl or NaOH. Thevolume of the tanks can be made up with deoxygenated water.

The bulk solutions were filled into 100 mL polypropylene bags with atarget fill volume of 100 mL and were then stoppered and sealed. Thebags were then further packaged in aluminum bags along with an oxygenscavenger, and were sealed.

The samples were tested for assay and impurities. TABLE 4 shows the fourdifferent formulations of pregabalin and acetaminophen in two differentbuffers in two different pH conditions, respectively.

TABLE 4 I J K L Citrate Citrate Acetate Phosphate Buffer Buffer BufferBuffer Composition (pH 5.5) (pH 6) (pH 5.5) (pH 6) (mg/mL) mg/mL mg/mLmg/mL mg/mL Acetaminophen 10 10 10 10   Pregabalin 4.5 4.5 4.5 4.5Sodium 5 4.5 5 5.5 Chloride Citric Acid 2.101 2.101 — — MonohydrateAcetic Acid — — 0.6 — Sodium — — — 1.2 Dihydrogen Phosphate HCl/NaOH 5Nq.s. 5.5 q.s. 6 q.s. 5.5 q.s. 6 Water for q.s 1 mL q.s 1 mL q.s 1 mL q.s1 mL Injection (WFI)

TABLES 5 and 6 provide assay values of pregabalin or acetaminophen,reflecting the remaining effectiveness of the pregabalin oracetaminophen in each solution described in TABLE 4.

In each tested solution, assay values of pregabalin or acetaminophenremained at least 98% or above after 2 weeks at 60° C. or after a monthat 40° C. or 25° C.

TABLE 5 PREGABALIN Assay 60° C. 40° C. 25° C. Buffers T0 1 Week 2 Week 1Month 1 Month Citrate Buffer pH 5.5 99.9 99 98.8 100.9 100.1 CitrateBuffer pH 6 100.6 99.8 104.1 101.3 101 Acetate Buffer pH 5.5 101 97.7102.1 100.8 101.1 Phosphate Buffer pH 6 99 99.9 101.4 101.9 100

TABLE 6 ACETAMINOPHEN Assay 60° C. 40° C. 25° C. Buffers T0 1 Week 2Week 1 Month 1 Month Citrate Buffer pH 5.5 100.2 107.1 103.6 101.2 100.7Citrate Buffer pH 6 99.8 101 105 101.3 99.9 Acetate Buffer pH 5.5 100.4101.3 103.3 102.3 100.5 Phosphate Buffer pH 6 99.7 100.4 103.4 101.3101.2

Determination of acetaminophen and pregabalin in the combined dosage wasperformed using RP-HPLC with UV detection at 205 nm. Separation of APAPand PGB from each other and impurities and degradants that were presentin the drug product was achieved by using a Thermo Scientific HypersilGOLD aQ column.

The chromatographic conditions utilized in this procedure were asfollows:

System Waters Alliance 2487 Column Thermo Scientific Hypersil GOLD aQcolumn, 5 μm, 4.6 × 250 mm Column 30 ± 3° C. Temperature Sample 5° C.Temperature Injection Volume 10 μL Flow Rate 1.5 mL/min Detection PDA/UVRun Time 34 Min Gradient Elution Time (min) A (%) B (%) 0 100 0 25.00 0100 28.00 0 100 28.01 100 0 34.00 100 0 Mobile Phase A 98% 0.01MPotassium Dihydrogen Phosphate in Water pH 7 Buffer: 2% AcetonitrileMobile Phase B 40% 0.01M Potassium Dihydrogen Phosphate in Water pH 7Buffer: 60% Acetonitrile

As shown in TABLES 7-9, the impurity levels were below detectablequantities when the solutions were stored at 40° C. (accelerated storagecondition) or lower temperatures. When the solutions were stored at 60°C., the carrier solutions at pH 6 produced fewer impurities than thesame conditions at pH 5.5.

For example, after one month, all of the tested samples were clear andcolorless and showed no signs of precipitation at 25 and 40° C. In theone-month samples at 25 and 40° C., acetaminophen and pregabalin assayvalues were about 100% and no 4-aminophenol and MPP levels wereobserved.

As can be further seen from TABLES 10 and 11, negligible amounts ofknown impurities 4-aminophenol and 4-(2-methylpropyl)pyrrolidin-2-one(MPP, also referred to as pregabalin lactam) and unknown impurities weredetected in the one-month month stability samples at 25 and 40° C.

TABLE 7 Related Substances (%)/RRT 60° C. T0 1 week 4- 4- Amino- Amino-phenol MPP Unknown Unknown Unknown Unknown phenol MPP Unknown Buffers(0.64) (2.34) (0.75) (1.223) (1.712) (1.936) (0.64) (2.34) (0.75)Citrate ND ND ND ND Nd ND 0.38 3.20 ND pH 5.5 Citrate ND ND ND ND Nd NDND 0.27 ND pH 6 Acetate ND ND ND ND Nd ND ND 1.69 ND pH 5.5 Phosphate NDND ND ND ND ND ND 0.47 ND pH 6 Related Substances (%)/RRT 60° C. 2 week4- 1 week Amino- Unknown Unknown Unknown phenol MPP Unknown UnknownUnknown Unknown Buffers (1.223) (1.712) (1.936) (0.64) (2.34) (0.75)(1.223) (1.712) (1.936) Citrate ND ND ND 0.07 3.99 0.39 ND ND ND pH 5.5Citrate ND ND ND ND 1.35 0.06 ND ND ND pH 6 Acetate 0.16 0.06 0.06 ND1.68 ND ND ND ND pH 5.5 Phosphate 0.08 ND ND ND 1.13 ND 0.07 ND 0.05 pH6 ND- Not Detected

TABLE 8 Related Substances (%)/RRT 40° C. T0 4- Amino- phenol MPPUnknown Unknown Unknown Unknown Buffers (0.64) (2.34) (0.75) (1.223)(1.712) (1.936) Citrate pH 5.5 ND ND ND ND ND ND Citrate pH 6 ND ND NDND ND ND Acetate pH 5.5 ND ND ND ND ND ND Phosphate pH 6 ND ND ND 0.05ND ND Related Substances (%)/RRT 40° C. 1 month 4- Amino- phenol MPPUnknown Unknown Unknown Unknown Buffers (0.64) (2.34) (0.75) (1.223)(1.712) (1.936) Citrate pH 5.5 ND ND ND ND ND ND Citrate pH 6 ND ND NDND ND ND Acetate pH 5.5 ND ND ND ND ND ND Phosphate pH 6 ND ND ND ND NDND ND-Not detected.

TABLE 9 Related Substances (%)/RRT 25° C. T0 4- Amino- phenol MPPUnknown Unknown Unknown Unknown Buffers (0.64) (2.34) (0.75) (1.223)(1.712) (1.936) Citrate pH 5.5 ND ND ND ND ND ND Citrate pH 6 ND ND NDND ND ND Acetate pH 5.5 ND ND ND ND ND ND Phosphate pH 6 ND ND ND 0.05ND ND Related Substances (%)/RRT 25° C. 1 month 4- Amino- phenol MPPUnknown Unknown Unknown Unknown Buffers (0.64) (2.34) (0.75) (1.223)(1.712) (1.936) Citrate pH 5.5 ND ND ND ND ND ND\ Citrate pH 6 ND ND NDND ND ND Acetate pH 5.5 ND ND ND ND ND ND Phosphate pH 6 ND ND ND ND NDND ND-Not detected.

Example 3: Pharmacokinetic Parameters of Acetaminophen-PregabalinCombination Formulations

Formulations for testing were prepared by weighing pregabalin and/oracetaminophen as indicated in TABLE 10 in a glass vial. The activeingredients were dissolved in 0.9% saline (20 mL) to achieve the desiredconcentration. The saline and vial constituents were mixed with bygentle swirling until a clear solution was obtained. The obtained clearsolution was filtered through a sterile 0.45 μm PVDF membrane syringefilter and then used for further studies.

TABLE 10 Drug/vial (mg) Group Acetaminophen Pregabalin Acetaminophen (10mg/mL) 200 — Pregabalin (0.75 mg/mL) — 15 Pregabalin (3 mg/mL) — 60Acetaminophen (10 mg/mL) & 200 15 Pregabalin (0.75 mg/mL) Acetaminophen(10 mg/mL) & 200 60 Pregabalin (3 mg/mL)

Pharmacokinetic parameters were analyzed after 15 min infusion ofacetaminophen, pregabalin, and acetaminophen and pregabalin combinationformulations in rats over a 24 h period (TABLE 11, FIG. 1—Acetaminophen; TABLE 12, FIG. 2 —Pregabalin).

The presence or absence of pregabalin did not affect thepharmacokinetics of acetaminophen in rats (TABLE 11; FIG. 1 ). No changein the pharmacokinetic profile of pregabalin was observed in thepresence or absence of acetaminophen (TABLE 12; FIG. 2 ).

When the general range for equivalence (80% to 125%) was determined,both parameters (C_(max) and AUC) were within the equivalence ranges.This finding further supported the lack of effect of either drug on thepharmacokinetic profile of the other drug. Therefore, the combination ofacetaminophen and pregabalin did not alter the Maximal BloodConcentration (C_(max)), nor the total exposure (AUC) compared to eitherdrug given alone.

TABLE 11 Equivalence (80%-125%) AUC_(0-∞) AUC_(0-∞) C_(max) (ng ·C_(max) (ng · Group (ng/mL) h/mL) (ng/mL) h/mL) APAP (17 mg/kg) 18,63311,482 14,906-23,291 9,186-14,353 Pregabalin 0 0 (1.25 mg/kg) Pregabalin0 0 (5 mg/kg) APAP (17 mg/kg) + 16,533 9,829 Pregabalin (1.25 mg/kg)APAP (17 mg/kg) + 18,500 10,928 Pregabalin (5 mg/kg)

TABLE 12 Equivalence (80%-125%) AUC_(0-∞) AUC_(0-∞) C_(max) (ng ·C_(max) (ng · Group (ng/mL) h/mL) (ng/mL) h/mL) APAP (17 mg/kg) 0 0Pregabalin 2,063 6,754 1,650-2,579 5,403-8,443 (1.25 mg/kg) Pregabalin7,908 26,126 6,326-9,885 20,901-32,658 (5 mg/kg) APAP (17 mg/kg) + 1,8586,455 Pregabalin (1.25 mg/kg) APAP (17 mg/kg) + 7,863 23,717 Pregabalin(5 mg/kg)

To evaluate the pharmacokinetic and toxicological profiles of thecombination formulations, rats were administered a 15 minute intravenousinfusion of acetaminophen (10 mg/mL), pregabalin (0.75 mg/mL),pregabalin (3 mg/mL), acetaminophen (10 mg/mL)+pregabalin (0.75 mg/mL),acetaminophen (10 mg/mL)+pregabalin (3 mg/mL), or a vehicle control.Blood samples were collected over a 24 h period, at which time the ratswere exsanguinated, and the blood was collected for clinical pathologyevaluation (chemistry, hematology, and coagulation). Finally, all theanimals were necropsied (all exterior and interior cavities and organswere examined), and the site of infusion in the jugular vein, lung,liver, and kidney underwent histopathologic evaluation.

Results from this study demonstrated that under the conditions of thisstudy, the combination formulation of acetaminophen and pregabalin didnot alter clinical pathology parameters (hematology—TABLE 13,coagulation—TABLE 14, clinical chemistry—TABLE 15). Further, no changeswere observed in the histopathology in any tissue sampled compared tothe vehicle control (as shown for lung in TABLE 16).

TABLE 13 APAP (17 mg/kg) + APAP (17 APAP PGB PGB mg/kg) + Hematology (17(1.25 PGB (1.25 PGB parameter Saline mg/kg) mg/kg) (5 mg/kg) mg/kg) (5mg/kg) WBC Mean 13.13 11.62 11.74 13.28 13.07 12.61 [×10³/μL] S.D. 1.862.62 1.62 1.65 3.41 1.4 Neutrophils Mean 1.44 1.69 1.4 1.52 1.45 1.64[×10³/μL] S.D. 0.61 0.82 0.55 0.34 0.45 0.76 Lymphocytes Mean 10.79 9.189.4 10.81 10.6 10.18 [×10³/μL] S.D. 1.55 1.58 1.08 1.53 3.08 0.85Monocytes Mean 0.45 0.3 0.5 0.45 0.46 0.42 [×10³/μL] S.D. 0.17 0.12 0.310.12 0.19 0.14 Eosinophils Mean 0.31 0.32 0.28 0.35 0.38 0.23 [×10³/μL]S.D. 0.06 0.16 0.11 0.19 0.09 0.12 Basophils Mean 0.08 0.07 0.08 0.080.09 0.07 [×10³/μL] S.D. 0.02 0.03 0.05 0.02 0.02 0.02 LGLUCLE Mean 0.070.06 0.10 0.08 0.1 0.07 [×10³/μL] S.D. 0.02 0.02 0.09 0.02 0.05 0.02 RBCMean 8.31 8.29 7.93 7.9 7.89 8.19 [×10⁶/μL] S.D. 0.49 0.6 0.18 0.18 0.310.59 Hemoglobin Mean 15.2 15.1 14.2 14.4 14.3 15.1 [g/dL] S.D. 0.9 0.80.3 0.5 0.8 0.7 Hematocrit Mean 48.6 47.7 44.2 45.1 44.5 47.8 [%] S.D.3.7 3.4 1 2.2 3 2.7 MCV Mean 58.5 57.6 55.8 57.1 56.3 58.4 [fL] S.D. 1.81.5 1 2.2 1.9 1.4 MCH Mean 18.3 18.2 17.8 18.3 18.1 18.5 [Pg] S.D. 0.30.5 0.2 0.5 0.4 0.7 MCHC Mean 31.2 31.6 32 32.1 32.1 31.6 [g/dL] S.D.0.7 0.6 0.5 0.5 0.4 0.4 Platelets Mean 885 883 908 933 992 964 [×10³/μL]S.D. 135 98 80 38 152 293 Reticulocytes Mean 5.02 4.37 4.11 * 4.7 4.275.04 [%] S.D. 0.16 0.74 0.51 0.4 0.22 0.54

TABLE 14 APAP (17 mg/kg) + APAP (17 APAP PGB PGB mg/kg) + Coagulation(17 (1.25 PGB (1.25 PGB parameter Saline mg/kg) mg/kg) (5 mg/kg) mg/kg)(5 mg/kg) Prothrombin Mean 16.6 16.6 16.8 16.6 17 16.5 time S.D. 0.6 0.90.7 0.7 0.7 0.5 [seconds] APPT Mean 13 13.3 12.9 12.4 12.4 12 [seconds]S.D. 0.5 1.2 1 1.6 0.4 1.6 WBC-white blood cell, LGLUCLE-large unstainedcell, RBC-red blood cell, MCV-mean cell volume, MCH-mean cellhemoglobin, MCHC-mean cell hemoglobin concentration. Saline: n = 5 pergroup, all others: n = 6 per group. APPT-Activated partialthromboplastin time. Saline: n = 5 per group, all others: n = 6 pergroup.

TABLE 15 APAP (17 mg/kg) + APAP (17 APAP PGB PGB mg/kg) + ClinicalChemistry (17 (1.25 PGB (1.25 PGB Parameter Saline mg/kg) mg/kg) (5mg/kg) mg/kg) (5 mg/kg) Sodium Mean 146 146 148 * 147 148 * 147 [mEq/L]S.D.  2  1  1  1  2  1 Potassium Mean  8.6  8.4  7.3  6.9 *  7.0 *  7.9[mEq/L] S.D.  1.3  0.9  0.3  0.2  0.6  1.4 Chloride Mean 102 102 102 101102 101 [mEq/L] S.D.  1  1  1  1  1   1 Albumin Mean  3.9  3.9  4.0  3.9 3.9   4.0 [g/dL] S.D.  0.1  0.1  0.2  0.1  0.1   0.1 ALP Mean 106  95 99  97  99  98 [U/L] S.D.  24  11  11  5  10  14 ALT Mean  59  48  45 51  48  50 [U/L] S.D.  16  10  5  6  9  6 AST Mean 133 102 *  22 ** 107105 * 104 * [U/L] S.D.  34  14   8  10  13  9 UREAN Mean  20  21  19  19 21  18 [mg/dL] S.D.  3  3  2  1  2  2 Calcium Mean  11.9  11.5  11.4 11.5  11.3  11.9 [mg/dL] S.D.  0.5  0.5  0.4  0.1  0.3  0.7 CholesterolMean  91  88  94  93  80  90 [mg/dL] S.D.  8  13  18  5  14  14Creatinine Mean  0.48  0.44  0.47  0.44  0.43  0.44 [mg/dL] S.D.  0.07 0.03  0.02  0.02  0.06  0.03 Glucose Mean 147 147 166 150 143 131[mg/dL] S.D.  24  25  27  16  22  34 PHOS Mean  12.5  11  10.6  10 ** 10.5 *  11.9 [mg/dL] S.D.  1.4  1.6  0.4  0.3  0.7  2.1 Bilirubin Mean 0.02  0.02  0.02  0.02  0.02  0.02 [mg/dL] S.D.  0  0  0  0.01  0  0.01Protein Mean  6.8  6.7  6.7  6.7  6.7  6.9 [g/dL] S.D.  0.2  0.2  0.3 0.2  0.1  0.2 Triglycerides Mean  32  32  33  30  28  30 [mg/dL] S.D. 9  9  10  6  6  5 GLOBUL Mean  2.8  2.8  2.8  2.8  2.8  2.9 [g/dL] S.D. 0.1  0.2  0.1  0.1  0.1  0.2 ALBGLOB Mean  1.4  1.4  1.4  1.4  1.4  1.4S.D.  0.1  0.1  0.1  0.1  0  0.1 ALP-alkaline phosphatase, ALT-alanineaminotransferase, AST-aspartate aminotransferase, UREAN-blood ureanitrogen, PHOS-inorganic phosphorus, GLOBUL-globulin (calculated),ALBGLOB-albumin/globulin ratio (calculated). n = 6 per group. * = p <0.05, ** = p < 0.01 by ANOVA-DUNNETT.

TABLE 16 APAP (17 APAP (17 APAP PGB PGB mg/kg) + mg/kg) + Necropsy (17(1.25 (5 PGB PGB Observation Saline mg/kg) mg/kg) mg/kg) (1.25 mg/kg) (5mg/kg) Lung Discolored 0 0 1 0 0 0 Focus 1 1 1 2 0 0 n = 6 per group.

Example 4: Analysis of Drug-Induced Autoimmune Hemolytic Anemia byCombination Formulation

Acetaminophen and pregabalin, alone or in combination, were evaluatedusing an in vitro hemolysis test with four biologic matrices (mouse,rat, dog, and human whole unclotted blood) to determine the hemolyticpotential for each compound on red blood cells.

The blood was mixed with either acetaminophen (5, 7.5, 10 mg/mL);pregabalin (0.75, 1.5, and 3 mg/mL); acetaminophen (10 mg/mL)+pregabalin(0.75, 1.5 and 3 mg/mL); a saline control; or a positive control (2%SDS), and incubated for 15 min at 37° C.

Based on the results of this study (TABLES 17 and 18), the combinationof acetaminophen and pregabalin did not cause hemolysis in the bloodfrom mice, rats, dogs, or humans under the tested conditions.

TABLE 17 % Hemolysis APAP APAP APAP Species (5 mg/mL) (7.5 mg/mL) (10mg/mL) Test Formulation 1 Mouse Blood 5 5 4 Rat Blood 6 0 2 Dog Blood 00 0 Human Blood 2 0 6 % Hemolysis PGB PGB PGB Species (0.75 mg/mL) (1.5mg/mL) (3 mg/mL) Test Formulation 2 Mouse Blood 0 4 0 Rat Blood 2 0 2Dog Blood 0 0 1 Human Blood 0 7 1 % Hemolysis APAP APAP APAP (10mg/mL) + (10 mg/mL) + (10 mg/mL) + PGB (0.75 PGB (1.5 PGB (3 Speciesmg/mL) mg/mL) mg/mL) Test Formulation 3 Mouse Blood 3 1 2 Rat Blood 8 80 Dog Blood 0 0 0 Human Blood 3 4 0

TABLE 18 Criteria for Determination of Hemolysis Percent HemolysisInterpretation <10% Not Hemolytic 10%-25% Relative Boundary (PossiblyHemolytic) >25% Hemolytic

Example 5: Pharmacodynamic Parameters of Combination Formulation

To determine the pharmacodynamic parameters of the combinationformulation, acetaminophen, pregabalin, or the combination, wereadministered to rats. The effect of the compounds on the rats wasassessed by the rotarod test.

To test the effect of pregabalin alone, different doses of pregabalin(5, 10, 20, 40, 60, 80 and 100 mg/kg), were administered to the rats asa 15 minute infusion. The effect of pregabalin on the motor control ofthe rats was assessed in groups of 5 male Sprague-Dawley rats. Vehicleand test agents were administered by intravenous infusion (IV-CI) over15 minutes starting 30 minutes before time 0 (15 minutes post-infusion).Chlorpromazine (30 mg/kg) was administered via oral gavage (PO) as apositive control 60 minutes before Time 0 to a group of rats that servedas a positive control for the experiment.

At Time 0 and 1 hour after Time 0, the rats were placed on theaccelerating rotarod, and the time (seconds) the rats remained on therotarod was recorded.

The results were analyzed by a one-way ANOVA followed by Dunnett's testfor comparison between vehicle control and test article/positive controlgroups. A p-value of less than 0.05, as shown with asterisk in FIG. 3 ,was considered to indicate a statistically significant inhibition ofmotor coordination. The inhibition of motor control indicated markedsomnolence/dizziness due to the effects of the test agent.

Further, the effect of pregabalin was tested with or withoutacetaminophen to see whether the combination of acetaminophen andpregabalin affected the pharmacodynamics of pregabalin.

Different doses of pregabalin (10, 20, or 40 mg/kg) with or withoutacetaminophen (50 mg/kg) were administered to the rats as a 15 minuteinfusion, and the effect of pregabalin on the motor control of the ratswas assessed in groups of 5 male Sprague-Dawley rats. Vehicle and testagents were administered by intravenous infusion (IV-CI) over 15 minutesstarting 30 minutes before Time 0 (15 minutes post infusion).Chlorpromazine (30 mg/kg) was administered via oral gavage (PO) 60minutes before Time 0 to a group of rats that served as a positivecontrol for the experiment. At Time 0 and 1 hour after Time 0, the ratswere placed on the accelerating rotarod, and the time (seconds) the ratremained on the rotarod was recorded.

Results were analyzed by a one-way ANOVA followed by Dunnett's test forcomparison between vehicle control and test article/positive controlgroups. A p-value of less than 0.05, as shown with asterisk in FIG. 4 ,was considered to indicate a statistically significant inhibition ofmotor coordination. The inhibition of motor control indicated markedsomnolence/dizziness due to the effects of the test agent.

Example 6: Analysis of the Effect on Somatic Pain of CombinationFormulation

The hot plate test was used to assess the effect on somatic pain afteradministration of pregabalin, acetaminophen, or a combinationformulation. Different doses of pregabalin (10, 20, or 40 mg/kg) with orwithout acetaminophen (50 mg/kg) were administered as a 15 minuteinfusion. The effect on somatic pain was tested in groups of 8 MaleSprague-Dawley rats.

Vehicle and test agents were administered by intravenous infusion(IV-CI) over 15 minutes starting 30 minutes before Time 0 (15 minutespost infusion). Morphine was used as a positive control, and wasadministered (3 mg/kg) by subcutaneous administration 60 minutes beforeTime 0. At Time 0 and 1 hour after Time 0, the rats were placed on astrong thermal stimulus at 52° C. (hot plate). The pain threshold of therats was assessed based on the time (seconds) required to elicit a pawwithdrawal response (latency).

The results are shown in FIG. 5 . The data were analyzed by a one-wayANOVA followed by Dunnett's test for comparison between vehicle controland test article/positive control groups. A p-value of less than 0.05indicated a statistically significant inhibition of the rats' ability todetect somatic pain from an external source. This result indicated thatthe combination of pregabalin and acetaminophen inhibited somatic pain.

As can be seen from FIG. 5 , the onset of the analgesic effect was (asexpected) near immediate for morphine. The onset for at least onecombination (50 mg/kg APAP; 40 mg/kg pregabalin) was relatively quick.FIG. 5 shows that the 50 mg/kg acetaminophen; 40 mg/kg pregabalinformulation increased the latency to about 16 seconds versus the initiallatency of about 8 seconds at baseline. Moreover, at least onecombination (50 mg/kg APAP; 40 mg/kg pregabalin) had a synergisticanalgesic effect that exceeded the effect and duration of analgesiaprovided by morphine.

Example 7: Analysis of Impurity Levels in Combination Formulation UsingDifferent Buffers and pH

Several formulations of acetaminophen and pregabalin were tested, inwhich the buffer and the pH were varied to determine the impurity levelin the formulations.

TABLE 19-25 show different combination formulations (A-G) ofacetaminophen and pregabalin that were tested in various buffers at pH5.5 or 6. TABLES 26-32 provide the impurities that were detected forboth pregabalin and acetaminophen. The number underneath each impurityin TABLES 26-32 indicates the relative retention time of the impurities.

TABLE 19 (A) Composition mg/mL Acetaminophen 10 Pregabalin 20 SodiumChloride 5.5 Sodium Dihydrogen Phosphate 1.87 NaOH 5N q.s. to pH 6 Water for Injection q.s. to 1 mL

TABLE 20 (B) Composition mg/mL Acetaminophen 10 Pregabalin 20 SodiumChloride 2.25 Citric Acid Monohydrate 2.101 NaOH 5N q.s. to pH 6  Waterfor Injection q.s. to 1 mL

TABLE 21 (C) Composition mg/mL Acetaminophen 10 Pregabalin 20 SodiumChloride 2.25 L-Histidine 1.55 NaOH 5N q.s. to pH 6  Water for Injectionq.s. to 1 mL

TABLE 22 (D) Composition mg/mL Acetaminophen 10 Pregabalin 4.5 SodiumChloride 5 Citric Acid Monohydrate 2.101 NaOH 5N q.s. to pH 5.5 Waterfor Injection q.s. to 1 mL 

TABLE 23 (E) Composition mg/mL Acetaminophen 10 Pregabalin 4.5 SodiumChloride 5 Citric Acid Monohydrate 2.101 NaOH 5N q.s. to pH 6  Water forInjection q.s. to 1 mL

TABLE 24 (F) Composition mg/mL Acetaminophen 10 Pregabalin 4.5 SodiumChloride 5 Acetic Acid 0.6 NaOH 5N q.s. to pH 5.5 Water for Injectionq.s. to 1 mL 

TABLE 25 (G) Composition mg/mL Acetaminophen 10 Pregabalin 4.5 SodiumChloride 5.5 Sodium Dihydrogen Phosphate 1.2 NaOH 5N q.s. to pH 6  Waterfor Injection q.s. to 1 mL

TABLE 26 (A) Results Related Substances (%)/RRT APAP 4-Amino- PGBOsmolality PGB APAP phenol Unk Unk Unk Unk Unk MPP Interval AppearancepH (mOsm) (%) (%) 0.64 0.7 1.1 1.11 1.38 2.69 2.34 0 time Clear, 6 39297 98.1 ND ND ND ND ND ND ND colorless liquid 1 Clear, 6.04 N/A 99.799.5 ND ND ND ND ND ND ND Month: colorless 25° C. liquid 1 Clear, 6.03N/A 99.8 100.4 ND ND ND ND ND ND ND Month: colorless 40° C. liquid 2Clear, 6.07 N/A 100.7 100.5 ND ND ND ND ND ND ND Months: colorless 25°C. liquid 2 Clear, 6.12 N/A 100.5 102 ND ND ND ND ND ND ND Months:colorless 40° C. liquid 3 Clear, 6.06 N/A 99 102 ND ND ND ND ND ND NDMonths: colorless 25° C. liquid 3 Clear, 6.06 N/A 99.9 99.8 ND ND ND NDND ND 0.1 Months: colorless 40° C. liquid 6 Clear, 6.07 N/A 98.2 102 NDND ND ND ND ND ND Months: colorless 25° C. liquid 6 Clear, 6.05 N/A100.2 104.3 ND ND ND ND ND ND 0.29 Months: colorless 40° C. liquid

TABLE 27 (B) Results APAP(%) Related Substances (%)/RRT APAP 4-Amino-PGB Osmolality phenol Unk Unk Unk Unk Unk MPP Interval Appearance pH(mOsm) PGB (%) 0.64 0.7 1.1 1.11 1.38 2.69 2.34 0 time Clear, 6 299 97.596.8 ND 0.14 ND ND ND ND ND colorless liquid 1 Clear, 6 N/A 99.4 99.3 NDND ND ND ND ND ND Month: colorless 25° C. liquid 1 Clear, 6.04 N/A 99.7100.8 ND ND ND ND ND ND ND Month: colorless 40° C. liquid 2 Clear, 6.07N/A 99 100.3 ND ND ND ND ND ND ND Months: colorless 25° C. liquid 2Clear, 6.08 N/A 100.7 101.2 ND ND ND ND ND ND ND Months: colorless 40°C. liquid 3 Clear, 6.05 N/A 99.3 100.5 ND ND ND ND ND ND ND Months:colorless 25° C. liquid 3 Clear, 6.06 N/A 100 101.2 ND ND ND ND ND ND0.07 Months: colorless 40° C. liquid 6 Clear, 6.05 N/A 98.6 102.6 ND NDND ND ND ND ND Months: colorless 25° C. liquid 6 Clear, 6.07 N/A 100.4104.6 ND ND ND ND ND ND 0.24 Months: colorless 40° C. liquid

TABLE 28 (C) Results APAP (%) Related Substances (%)/RRT APAP 4-Amino-PGB Osmolality phenol Unk Unk Unk Unk Unk MPP Interval Appearance pH(mOsm) PGB (%) 0.64 0.7 1.1 1.11 1.38 2.69 2.34 0 time Clear, 6.02 28497.2 98.4 ND ND ND ND ND ND ND colorless liquid 1 Clear, 6.01 N/A 99.8100 ND ND ND ND ND ND ND Month: colorless 25° C. liquid 1 Clear, 6.02N/A 99.8 100.6 ND ND ND ND ND ND ND Month: colorless 40° C. liquid 2Clear, 6.1 N/A 99.4 99.9 ND ND ND ND ND ND ND Months: colorless liquid 2Clear, 6.1 N/A 99.8 100.8 ND ND ND ND ND ND ND Months: yellow 40° C.colored liquid 3 Clear, 6.09 N/A 99.3 101.5 ND ND ND ND ND ND ND Months:colorless 25° C. liquid 3 Pale yellow 6.09 N/A 100 100.2 ND ND ND ND NDND 0.06 Months: colored 40° C. liquid 6 Clear, 6.09 N/A 98.6 102.5 ND NDND ND ND ND ND Months: colorless 25° C. liquid 6 Clear, 6.08 N/A 100.6103.8 ND ND ND ND ND ND 0.23 Months: colorless 40° C. liquid

TABLE 29 (D) Results APAP(%) Related Substances (%)/RRT APAP 4-Amino-PGB Osmolality phenol Unk Unk Unk Unk Unk MPP Interval Appearance pH(mOsm/Kg) PGB (%) 0.64 0.75 1.22 1.38 1.71 1.94 2.34 0 time Clear, 5.5282 99.9 100.2 ND ND ND ND ND ND ND colorless liquid 1 Clear, 5.52 N/A100.1 100.7 ND ND ND ND ND ND ND Month: colorless 25° C. liquid 1 Clear,5.52 N/A 100.9 101.2 ND ND ND ND ND ND ND Month: colorless 40° C. liquid2 Clear, 5.52 N/A 99.9 97.8 ND ND ND ND ND ND ND Months: colorless 25°C. liquid 2 Clear, 5.55 N/A 99.9 98.4 ND ND ND ND ND ND ND Months:colorless 40°C. liquid 3 Clear, 5.54 N/A 101.7 99.4 ND ND ND ND ND ND NDMonths: colorless 25°C. liquid 3 Clear, 5.52 N/A 100.4 99.6 ND ND ND NDND ND 0.19 Months: colorless 40° C. liquid

TABLE 30 (E) Results APAP(%) Related Substances (%)/RRT APAP 4-Amino-PGB Osmolality phenol Unk Unk Unk Unk Unk MPP Interval Appearance pH(mOsm/Kg) PGB (%) 0.64 0.75 1.22 1.38 1.71 1.94 2.34 0 time Clear, 6 268100.6 99.8 ND ND ND ND ND ND ND colorless liquid 1 Clear, 6.02 N/A 10199.9 ND ND ND ND ND ND ND Month: colorless 25° C. liquid 1 Clear, 6.02N/A 101.3 101.3 ND ND ND ND ND ND ND Month: colorless 40° C. liquid 2Clear, 6.05 N/A 99.8 98.3 ND ND ND ND ND ND ND Months: colorless 25° C.liquid 2 Clear, 6.01 N/A 99.6 99.3 ND ND ND 0.13 ND ND 0.17 Months:colorless 40° C. liquid 3 Clear, 6.02 N/A 101.4 98.9 ND ND ND ND ND NDND Months: colorless 25° C. liquid 3 Clear, 6.04 N/A 99.9 99.3 ND ND NDND ND ND 0.09 Months: colorless 40° C. liquid

TABLE 31 (F) Results APAP(%) Related Substances (%)/RRT APAP 4-Amino-PGB Osmolality phenol Unk Unk Unk Unk Unk MPP Interval Appearanc pH(mOsm/Kg) PGB (%) 0.64 0.75 1.22 1.38 1.71 1.94 2.34 0 time Clear, 5.52273 101 100.4 ND ND ND ND ND ND ND colorless liquid 1 Clear, 5.52 N/A101.1 100.5 ND ND ND ND ND ND ND Month: colorless 25° C. liquid 1 Clear,5.51 N/A 100.8 102.3 ND ND ND ND ND ND ND Month: colorless 40° C. liquid2 Clear, 5.5 N/A 98.9 98.6 ND ND ND ND ND ND ND Months: colorless 25° C.liquid 2 Clear, 5.5 N/A 99.8 98.7 ND ND ND 0.13 ND ND 0.19 Months:colorless 40° C. liquid 3 Clear, 5.54 N/A 100.4 99.1 ND ND ND ND ND NDND Months: colorless 25° C. liquid 3 Clear, 5.54 N/A 98.9 99.5 ND ND NDND ND ND 0.15 Months: colorless 40° C. liquid

TABLE 32 (G) Results APAP(%) Related Substances (%)/RRT APAP 4-Amino-PGB Osmolality phenol Unk Unk Unk Unk Unk MPP Interval Appearance pH(mOsm/Kg) PGB (%) 0.64 0.75 1.22 1.38 1.71 1.94 2.34 0 time Clear, 6.02292 99 99.7 ND ND 0.05 ND ND ND ND colorless liquid 1 Clear, 6.03 N/A100 101.2 ND ND ND ND ND ND ND Month: colorless 25° C. liquid 1 Clear,6.03 N/A 101.9 101.3 ND ND ND ND ND ND ND Month: colorless 40° C. liquid2 Clear, 6.05 N/A 98.2 98.8 ND ND ND ND ND ND ND Months: colorless 25°C. liquid 2 Clear, 6.04 N/A 98.4 97 ND ND ND ND ND ND ND Months:colorless 40° C. liquid 3 Clear, 6.04 N/A 101.2 98.2 ND ND ND ND ND NDND Months: colorless 25° C. liquid 3 Clear, 6.04 N/A 101.4 100 ND ND0.05 ND ND ND 0.08 Months colorless 40° C. liquid

The results above indicate that all of the formulations remained asclear, colorless liquids after 3 or 6 months at the accelerateddegradation condition of 40° C. The results also indicated that thetested samples demonstrated minimal fluctuation in pH over theexperimental time periods, nor was there a significant increase inimpurities over the experimental time period.

Embodiments

The following non-limiting embodiments provide illustrative examples ofthe invention, but do not limit the scope of the invention.

Embodiment 1. A pharmaceutical composition comprising, in a liquid unitdosage form: a) a gabapentinoid; b) acetaminophen; c) a pH-adjustingagent; and d) water.

Embodiment 2. The pharmaceutical composition of embodiment 1, whereinthe gabapentinoid is gabapentin, or a pharmaceutically acceptable saltthereof.

Embodiment 3. The pharmaceutical composition of embodiment 1, whereinthe gabapentinoid is pregabalin, or a pharmaceutically acceptable saltthereof.

Embodiment 4. The pharmaceutical composition of any one of embodiments1-3, wherein the liquid unit dosage form further comprises an acid, aconjugate base of the acid, or both the acid and the conjugate base ofthe acid.

Embodiment 5. The pharmaceutical composition of embodiment 4, whereinthe acid is citric acid.

Embodiment 6. The pharmaceutical composition of embodiment 4, whereinthe acid is acetic acid.

Embodiment 7. The pharmaceutical composition of embodiment 4, whereinthe acid is phosphoric acid.

Embodiment 8. The pharmaceutical composition of any one of embodiments1-7, wherein the liquid unit dosage form further comprises anisotonicity inducing agent.

Embodiment 9. The pharmaceutical composition of embodiment 8, whereinthe isotonicity inducing agent is sodium chloride.

Embodiment 10. The pharmaceutical composition of embodiment 8, whereinthe isotonicity inducing agent is mannitol.

Embodiment 11. The pharmaceutical composition of any one of embodiments1-10, wherein the pH-adjusting agent is sodium hydroxide.

Embodiment 12. The pharmaceutical composition of any one of embodiments1-10, wherein the pH-adjusting agent is hydrochloric acid.

Embodiment 13. The pharmaceutical composition of any one of embodiments1-12, wherein the gabapentinoid is present in the liquid unit dosageform in an amount from about 0.1 mg/mL to about 50 mg/mL.

Embodiment 14. The pharmaceutical composition of any one of embodiments1-13, wherein the acetaminophen is present in the liquid unit dosageform in an amount from about 2 mg/mL to about 20 mg/mL.

Embodiment 15. The pharmaceutical composition of any one of embodiments1-14, wherein the liquid unit dosage form further comprises adecomposition product of the gabapentinoid at a level of no more thanabout 5%.

Embodiment 16. The pharmaceutical composition of embodiment 15, whereinthe decomposition product of the gabapentinoid is4-(2-methylpropyl)pyrrolidin-2-one.

Embodiment 17. The pharmaceutical composition of any one of embodiments1-16, wherein the liquid unit dosage form further comprises adecomposition product of the acetaminophen at a level of no more thanabout 0.5%.

Embodiment 18. The pharmaceutical composition of embodiment 17, whereinthe decomposition product of the acetaminophen is 4-aminophenol.

Embodiment 19. The pharmaceutical composition of any one of embodiments1-18, wherein the liquid unit dosage form has a pH of about 4 to about7.

Embodiment 20. The pharmaceutical composition of embodiment 19, whereinthe pH of the liquid unit dosage form is about 5.

Embodiment 21. The pharmaceutical composition of embodiment 19, whereinthe pH of the liquid unit dosage form is about 5.5

Embodiment 22. The pharmaceutical composition of embodiment 19, whereinthe pH of the liquid unit dosage form is about 6.

Embodiment 23. The pharmaceutical composition of embodiment 1, whereinthe liquid unit dosage form further comprises: e) an acid, a conjugatebase of the acid, or both the acid and the conjugate base of the acid;f) sodium chloride; g) a decomposition product of the gabapentinoid; andh) a decomposition product of the acetaminophen.

Embodiment 24. The pharmaceutical composition of embodiment 1, whereinthe liquid unit dosage form comprises: a) the gabapentinoid, wherein thegabapentinoid is pregabalin, or a pharmaceutically acceptable saltthereof, wherein the pregabalin is present in the liquid unit dosageform in an amount of about 0.1 to about 20 mg/mL; b) the acetaminophen,wherein the acetaminophen is present in the liquid unit dosage form inan amount of about 10 mg/mL; c) the pH-adjusting agent, wherein thepH-adjusting agent is sodium hydroxide; d) about 1.87 mg/mL sodiumdihydrogen phosphate; e) about 5.5 mg/mL sodium chloride; and f) water,wherein the liquid unit dosage form has a pH of about 5 to about 7.

Embodiment 25. The pharmaceutical composition of embodiment 24, whereinthe pH of the liquid unit dosage form is about 6.

Embodiment 26. The pharmaceutical composition of embodiment 1, whereinthe liquid unit dosage form comprises: a) the gabapentinoid, wherein thegabapentinoid is pregabalin, or a pharmaceutically acceptable saltthereof, wherein the pregabalin is present in the liquid unit dosageform in an amount of about 0.1 to about 20 mg/mL; b) the acetaminophen,wherein the acetaminophen is present in the liquid unit dosage form inan amount of about 10 mg/mL; c) the pH-adjusting agent, wherein thepH-adjusting agent is sodium hydroxide; d) about 2.101 mg/mL citric acidmonohydrate; e) about 2.25 mg/mL sodium chloride; and f) water, whereinthe liquid unit dosage form has a pH of about 5 to about 7.

Embodiment 27. The pharmaceutical composition of embodiment 26, whereinthe pH of the liquid unit dosage is about 6.

Embodiment 28. The pharmaceutical composition of embodiment 1, whereinthe liquid unit dosage form comprises: a) the gabapentinoid, wherein thegabapentinoid is pregabalin, or a pharmaceutically acceptable saltthereof, wherein the pregabalin is present in the liquid unit dosageform in an amount of about 0.1 to about 20 mg/mL; b) the acetaminophen,wherein the acetaminophen is present in the liquid unit dosage form inan amount of about 10 mg/mL; c) the pH-adjusting agent, wherein thepH-adjusting agent is sodium hydroxide; d) about 1.55 mg/mL L-Histidine;e) about 2.25 mg/mL sodium chloride; and f) water, wherein the liquidunit dosage form has a pH of about 5 to about 7.

Embodiment 29. The pharmaceutical composition of embodiment 28, whereinthe pH of the liquid unit dosage form is about 6.

Embodiment 30. The pharmaceutical composition of embodiment 1, whereinthe liquid unit dosage form comprises: a) the gabapentinoid, wherein thegabapentinoid is pregabalin, or a pharmaceutically acceptable saltthereof, wherein the pregabalin is present in the liquid unit dosageform in an amount of about 0.1 to about 20 mg/mL; b) the acetaminophen,wherein the acetaminophen is present in the liquid unit dosage form inan amount of about 10 mg/mL; c) the pH-adjusting agent, wherein thepH-adjusting agent is sodium hydroxide; d) about 2.101 mg/mL citric acidmonohydrate; e) about 5 mg/mL sodium chloride; and f) water, wherein theliquid unit dosage form has a pH of about 5 to about 7.

Embodiment 31. The pharmaceutical composition of embodiment 30, whereinthe pH of the liquid unit dosage form is about 5.5.

Embodiment 32. The pharmaceutical composition of embodiment 1, whereinthe liquid unit dosage form comprises: a) the gabapentinoid, wherein thegabapentinoid is pregabalin, or a pharmaceutically acceptable saltthereof, wherein the pregabalin is present in the liquid unit dosageform in an amount of about 0.1 to about 20 mg/mL; b) the acetaminophen,wherein the acetaminophen is present in the liquid unit dosage form inan amount of about 10 mg/mL; c) the pH-adjusting agent, wherein thepH-adjusting agent is sodium hydroxide; d) about 0.6 mg/mL acetic acid;e) about 5 mg/mL sodium chloride; and f) water, wherein the liquid unitdosage form has a pH of about 5 to about 7.

Embodiment 33. The pharmaceutical composition of embodiment 32, whereinthe pH of the liquid unit dosage form is about 5.5.

Embodiment 34. The pharmaceutical composition of embodiment 1, whereinthe liquid unit dosage form comprises: a) the gabapentinoid, wherein thegabapentinoid is pregabalin, or a pharmaceutically acceptable saltthereof, wherein the pregabalin is present in the liquid unit dosageform in an amount of about 0.1 to about 20 mg/mL; b) the acetaminophen,wherein the acetaminophen is present in the liquid unit dosage form inan amount of about 10 mg/mL; c) the pH-adjusting agent, wherein thepH-adjusting agent is sodium hydroxide; d) about 1.2 mg/mL sodiumdihydrogen phosphate; e) about 5.5 mg/mL sodium chloride; and f) water,wherein the liquid unit dosage form has a pH of about 5 to about 7.

Embodiment 35. The pharmaceutical composition of embodiment 34, whereinthe pH of the liquid unit dosage form is about 6.

Embodiment 36. The pharmaceutical composition of embodiment 1, whereinthe liquid unit dosage form further comprises an impurity, wherein theimpurity is determined based on: (a) injecting the liquid unit dosageform into a high performance liquid chromatography apparatus, whereinthe apparatus comprises: (i) a chromatography column containingadsorbent particles as a stationary phase; (ii) a first mobile phasepassing through the chromatography column, wherein the first mobilephase is aqueous potassium dihydrogen phosphate at pH 7 with 2%acetonitrile; and (iii) a second mobile phase passing through thechromatography column, wherein the second mobile phase is aqueouspotassium dihydrogen phosphate at pH 7 with 60% acetonitrile; (b)running the liquid unit dosage form through the chromatography columnfor 34 minutes; (c) eluting the impurity from the chromatography columnusing a gradient of the first mobile phase, and a gradient of the secondmobile phase, wherein each of the first mobile phase and second mobilephase are run at a flow rate of 1.5 mL/min through the chromatographycolumn; (d) passing the impurity through a UV detector to generate a UVspectrum of the eluted unit dosage form and the impurity; (e)identifying the impurity based on a retention time of the impurityrelative to a standard; and (f) calculating an amount of the impuritybased on an integration of a peak obtained for the impurity from the UVspectrum.

Embodiment 37. The pharmaceutical composition of any one of embodiments1-35, wherein the pharmaceutical composition is formulated for packagingin a bag, a glass vial, or a prefilled syringe.

Embodiment 38. The pharmaceutical composition of embodiment 37, whereinthe pharmaceutical composition is formulated for packaging in a bag,wherein the bag is a polymer bag.

Embodiment 39. The pharmaceutical composition of embodiment 38, whereinthe polymer bag is a polypropylene bag, and the polypropylene bag isfurther packaged in an aluminum over-pouch.

Embodiment 40. The pharmaceutical composition of embodiment 39, whereinthe aluminum over-pouch contains an oxygen scavenger.

Embodiment 41. A method of treating pain in a subject in need thereof,the method comprising administering to the subject atherapeutically-effective amount of a liquid unit dosage form, whereinthe liquid unit dosage form comprises: a) a gabapentinoid; b)acetaminophen; c) a pH-adjusting agent; and d) water.

Embodiment 42. The method of embodiment 41, wherein the gabapentinoid isgabapentin, or a pharmaceutically acceptable salt thereof.

Embodiment 43. The method of embodiment 41, wherein the gabapentinoid ispregabalin, or a pharmaceutically acceptable salt thereof.

Embodiment 44. The method of any one of embodiments 41-43, wherein theliquid unit dosage form further comprises an acid, a conjugate base ofthe acid, or both the acid and the conjugate base of the acid.

Embodiment 45. The method of embodiment 44, wherein the acid is citricacid.

Embodiment 46. The method of embodiment 44, wherein the acid is aceticacid.

Embodiment 47. The method of embodiment 44, wherein the acid isphosphoric acid.

Embodiment 48. The method of any one of embodiments 41-47, wherein theliquid unit dosage form further comprises an isotonicity inducing agent.

Embodiment 49. The method of embodiment 48, wherein the isotonicityinducing agent is sodium chloride.

Embodiment 50. The method of embodiment 48, wherein the isotonicityinducing agent is mannitol.

Embodiment 51. The method of any one of embodiments 41-50, wherein thepH-adjusting agent is sodium hydroxide.

Embodiment 52. The method of any one of embodiments 41-50, wherein thepH-adjusting agent is hydrochloric acid.

Embodiment 53. The method of any one of embodiments 41-52, wherein thegabapentinoid is present in the liquid unit dosage form in an amountfrom about 0.1 mg/mL to about 50 mg/mL.

Embodiment 54. The method of any one of embodiments 41-52, wherein theacetaminophen in present in the liquid unit dosage form in an amountfrom about 2 mg/mL to about 20 mg/mL.

Embodiment 55. The method of any one of embodiments 41-54, wherein theliquid unit dosage form further comprises a decomposition product of thegabapentinoid at a level of no more than about 5%.

Embodiment 56. The method of embodiment 55, wherein the decompositionproduct of the gabapentinoid is 4-(2-methylpropyl)pyrrolidin-2-one.

Embodiment 57. The method of any one embodiments 41-56, wherein theliquid unit dosage form further comprises a decomposition product of theacetaminophen at a level of no more than 0.5%.

Embodiment 58. The method of embodiment 57, wherein the decompositionproduct of the acetaminophen is 4-aminophenol.

Embodiment 59. The method of any one of embodiments 41-58, wherein theliquid unit dosage form has a pH of about 4 to about 7.

Embodiment 60. The method of embodiment 59, wherein the pH of the liquidunit dosage form is about 5.

Embodiment 61. The method of embodiment 59, wherein the pH of the liquidunit dosage form is about 5.5.

Embodiment 62. The method of embodiment 59, wherein the pH of the liquidunit dosage form is about 6.

Embodiment 63. The method of any one of embodiments 41-62, wherein thepain is postoperative pain.

Embodiment 64. The method of any one of embodiments 41-63, wherein theliquid unit dosage form is administered to the subject within 24 hoursprior to the subject undergoing a surgical procedure.

Embodiment 65. The method of any one of embodiments 41-63, wherein theliquid unit dosage form is administered to the subject simultaneouslywith the subject undergoing a surgical procedure.

Embodiment 66. The method of any one of embodiments 41-63, wherein theliquid unit dosage form is administered to the subject within 24 hoursafter the subject has undergone a surgical procedure.

Embodiment 67. The method of any one of embodiments 41-66, wherein theadministration is intravenous administration.

Embodiment 68. The method of any one of embodiments 41-66, wherein theadministration is intramuscular administration.

Embodiment 69. The method of any one of embodiments 41-66, wherein theadministration is subcutaneous administration.

Embodiment 70. A method of manufacturing a pharmaceutical formulation,the method comprising: a) adding water to a manufacturing tank; b)deoxygenating the water in the manufacturing tank by sparging nitrogento achieve a dissolved oxygen level of less than about 1 ppm; c) addinga buffer to the water in the manufacturing tank to provide a mixture; d)adding a pH-adjusting agent to the mixture in the manufacturing tank,wherein the adding the pH-adjusting agent to the mixture in themanufacturing tank adjusts a pH of the mixture to about pH 4 to about pH7; e) disposing a gabapentinoid into the mixture in the manufacturingtank; and f) disposing acetaminophen into the mixture in themanufacturing tank.

Embodiment 71. The method of embodiment 70, further comprising removinga portion of the mixture from the manufacturing tank and packaging theportion of the mixture that was removed from the manufacturing tank in acontainer.

Embodiment 72. The method of embodiment 71, wherein the container is apolymer bag.

Embodiment 73. The method of embodiment 71, wherein the container is aglass vial or a prefilled syringe.

Embodiment 74. The method of embodiment 72, wherein the polymer bag is apolypropylene bag, and the polypropylene bag is further packaged in analuminum over-pouch.

Embodiment 75. The method of embodiment 74, wherein the aluminumover-pouch contains an oxygen scavenger.

Embodiment 76. The method of any one of embodiments 70-75, wherein thegabapentinoid is gabapentin, or a pharmaceutically acceptable saltthereof.

Embodiment 77. The method of any one of embodiments 70-75, wherein thegabapentinoid is pregabalin, or a pharmaceutically acceptable saltthereof.

Embodiment 78. The method of any one of embodiments 70-77, wherein thepH-adjusting agent is sodium hydroxide.

Embodiment 79. The method of any one of embodiments 70-77, wherein thepH-adjusting agent is hydrochloric acid.

Embodiment 80. The method of embodiment 72, 74, or 75, wherein thegabapentinoid is present in the polymer bag in an amount from about 0.1mg/mL to about 50 mg/mL.

Embodiment 81. The method of embodiment 73, wherein the gabapentinoid ispresent in the glass vial in an amount from about 0.1 mg/mL to about 50mg/mL.

Embodiment 82. The method of embodiment 72, 74, or 75, wherein theacetaminophen in present in the polymer bag in an amount from about 2mg/mL to about 20 mg/mL.

Embodiment 83. The method of embodiment 73, wherein the acetaminophen inpresent in the glass vial in an amount from about 2 mg/mL to about 20mg/mL.

Embodiment 100. A pharmaceutical composition, comprising in a liquidunit dosage form: a) a gabapentinoid, or a pharmaceutically acceptablesalt thereof b) acetaminophen; c) a pH-adjusting agent; and d) water,wherein the liquid unit dosage form has a pH of about 4.5, and whereinupon storage of the liquid unit dosage form at about 60° C. for at leastabout two weeks, the liquid unit dosage form exhibits less than about 2%degradation.

Embodiment 101. A pharmaceutical composition, comprising in a liquidunit dosage form: a) a gabapentinoid, or a pharmaceutically acceptablesalt thereof b) acetaminophen; c) a pH-adjusting agent; and d) water,wherein the liquid unit dosage form has a pH of about 4.5, and whereinupon storage of the liquid unit dosage form at about 40° C. for at leastabout one month, the liquid unit dosage form exhibits less than about 2%degradation.

Embodiment 102. A pharmaceutical composition, comprising in a liquidunit dosage form: a) a gabapentinoid, or a pharmaceutically acceptablesalt thereof b) acetaminophen; c) a pH-adjusting agent; and d) water,wherein the liquid unit dosage form has a pH of about 4.5, and whereinupon storage of the liquid unit dosage form at about 25° C. for at leastabout one month, the liquid unit dosage form exhibits less than about 2%degradation.

Embodiment 103. A pharmaceutical composition, comprising in a liquidunit dosage form: a) a gabapentinoid, or a pharmaceutically acceptablesalt thereof; b) acetaminophen; c) a pH-adjusting agent; and d) water,wherein the liquid unit dosage form has a pH of about 5 to about 6, andwherein upon storage of the liquid unit dosage form at about 60° C. forat least about two weeks, the liquid unit dosage form comprises no morethan about 5% of 4-(2-methylpropyl)pyrrolidin-2-one.

Embodiment 104. A pharmaceutical composition, comprising in a liquidunit dosage form: a) a gabapentinoid, or a pharmaceutically acceptablesalt thereof; b) acetaminophen; c) a pH-adjusting agent; and d) water,wherein the liquid unit dosage form has a pH of about 6, and whereinupon storage of the liquid unit dosage form at about 60° C. for at leastabout two weeks, the liquid unit dosage form comprises no more thanabout 1% of 4-aminophenol.

Embodiment 105. A pharmaceutical composition, comprising in a liquidunit dosage form: a) a gabapentinoid, or a pharmaceutically acceptablesalt thereof; b) acetaminophen; c) a pH-adjusting agent; and d) water,wherein the liquid unit dosage form has a pH of about 5 to about 6, andwherein upon storage of the liquid unit dosage form at about 60° C. forat least about two weeks, the liquid unit dosage form comprises no morethan about 0.5% of 4-aminophenol.

Embodiment 106. A pharmaceutical composition, comprising in a liquidunit dosage form: a) a gabapentinoid, or a pharmaceutically acceptablesalt thereof; b) acetaminophen; c) a pH-adjusting agent; and d) water,wherein the liquid unit dosage form has a pH of about 6, and whereinupon storage of the liquid unit dosage form at about 60° C. for at leastabout two weeks, the liquid unit dosage form comprises no more thanabout 2% of 4-(2-methylpropyl)pyrrolidin-2-one.

Embodiment 107. A pharmaceutical composition, comprising in a liquidunit dosage form: a) a gabapentinoid, or a pharmaceutically acceptablesalt thereof; b) acetaminophen; c) a pH-adjusting agent; and d) water,wherein the liquid unit dosage form has a pH of about 6, and whereinupon storage of the liquid unit dosage form at about 40° C. for at leastabout six months, the liquid unit dosage form comprises no more thanabout 0.5% of 4-(2-methylpropyl)pyrrolidin-2-one.

Embodiment 108. A pharmaceutical composition, comprising in a liquidunit dosage form: a) a gabapentinoid, or a pharmaceutically acceptablesalt thereof; b) acetaminophen; c) citric acid monohydrate; and d)water, wherein the liquid unit dosage form has a pH of about 6, andwherein upon storage of the liquid unit dosage form at about 60° C. forat least about two weeks, the liquid unit dosage form comprises no morethan about 7% of 4-(2-methylpropyl)pyrrolidin-2-one.

Embodiment 109. A pharmaceutical composition, comprising in a liquidunit dosage form: a) a gabapentinoid, or a pharmaceutically acceptablesalt thereof; b) acetaminophen; c) L-Histidine; and d) water, whereinthe liquid unit dosage form has a pH of about 6, and wherein uponstorage of the liquid unit dosage form at about 60° C. for at leastabout two weeks, the liquid unit dosage form comprises no more thanabout 3% of 4-(2-methylpropyl)pyrrolidin-2-one.

Embodiment 110. A pharmaceutical composition, comprising in a liquidunit dosage form: a) a gabapentinoid, or a pharmaceutically acceptablesalt thereof; b) acetaminophen; c) a pH-adjusting agent; and d) water,wherein the liquid unit dosage form has a pH of about 5.5, and whereinupon storage of the liquid unit dosage form at about 60° C. for at leastabout two weeks, the liquid unit dosage form comprises no more thanabout 0.5% of 4-aminophenol.

Embodiment 111. A pharmaceutical composition, comprising in a liquidunit dosage form: a) a gabapentinoid, or a pharmaceutically acceptablesalt thereof; b) acetaminophen; c) a pH-adjusting agent; and d) water,wherein the liquid unit dosage form has a pH of about 5.5, and whereinupon storage of the liquid unit dosage form at about 60° C. for at leastabout two weeks, the liquid unit dosage form comprises no more thanabout 4% of 4-(2-methylpropyl)pyrrolidin-2-one.

Embodiment 112. A pharmaceutical composition, comprising in a liquidunit dosage form: a) a gabapentinoid, or a pharmaceutically acceptablesalt thereof; b) acetaminophen; c) a pH-adjusting agent; and d) water,wherein the liquid unit dosage form has a pH of about 5.5, and whereinupon storage of the liquid unit dosage form at about 40° C. for at leastabout six months, the liquid unit dosage form comprises no more thanabout 0.5% of 4-(2-methylpropyl)pyrrolidin-2-one.

Embodiment 113. A pharmaceutical composition, comprising in a liquidunit dosage form: a) a gabapentinoid, or a pharmaceutically acceptablesalt thereof; b) acetaminophen; c) acetic acid; and d) water, whereinthe liquid unit dosage form has a pH of about 5.5, and wherein uponstorage of the liquid unit dosage form at about 60° C. for at leastabout two weeks, the liquid unit dosage form comprises no more thanabout 2% of 4-(2-methylpropyl)pyrrolidin-2-one.

What is claimed is:
 1. A method of treating pain in a subject in needthereof, the method comprising administering to the subject atherapeutically-effective amount of a liquid unit dosage form, whereinthe liquid unit dosage form comprises: a) a gabapentinoid, wherein thegabapentinoid is pregabalin, or a pharmaceutically acceptable saltthereof; b) acetaminophen; c) a pH-adjusting agent; and d) water;wherein the liquid unit dosage form has a pH of between 5 and 7; whereinthe gabapentinoid is present in the liquid unit dosage form in an amountfrom about 0.1 mg/mL to about 50 mg/mL; and wherein the acetaminophen ispresent in the liquid unit dosage form in an amount from about 2 mg/mLto about 20 mg/mL.
 2. The method of claim 1, wherein the gabapentinoidis the pharmaceutically acceptable salt of pregabalin.
 3. The method ofclaim 1, wherein the liquid unit dosage form further comprises an acid,a conjugate base of the acid, or both the acid and the conjugate base ofthe acid.
 4. The method of claim 3, wherein the acid is citric acid,acetic acid, or phosphoric acid.
 5. The method of claim 1, wherein theliquid unit dosage form further comprises an isotonicity inducing agent.6. The method of claim 5, wherein the isotonicity inducing agent issodium chloride or mannitol.
 7. The method of claim 1, wherein thepH-adjusting agent is sodium hydroxide.
 8. The method of claim 1,wherein the pH-adjusting agent is hydrochloric acid.
 9. The method ofclaim 1, wherein the gabapentinoid is present in the liquid unit dosageform in an amount from about 0.1 mg/mL to about 50 mg/mL.
 10. The methodof claim 1, wherein the acetaminophen in present in the liquid unitdosage form in an amount from about 2 mg/mL to about 20 mg/mL.
 11. Themethod of claim 1, wherein the liquid unit dosage form further comprisesa decomposition product of the gabapentinoid at a level of no more thanabout 5%.
 12. The method of claim 11, wherein the decomposition productof the gabapentinoid is 4-(2-methylpropyl)pyrrolidin-2-one.
 13. Themethod of claim 1, wherein the liquid unit dosage form further comprisesa decomposition product of the acetaminophen at a level of no more thanabout 0.5%.
 14. The method of claim 13, wherein the decompositionproduct of the acetaminophen is 4-aminophenol.
 15. The method of claim1, wherein the pH of the liquid unit dosage form is
 5. 16. The method ofclaim 1, wherein the pH of the liquid unit dosage form is about 5.5. 17.The method of claim 1, wherein the pH of the liquid unit dosage form isabout
 6. 18. The method of claim 1, wherein the pain is postoperativepain.
 19. The method of claim 1, wherein the liquid unit dosage form isadministered to the subject within 24 hours prior to the subjectundergoing a surgical procedure.
 20. The method of claim 1, wherein theliquid unit dosage form is administered to the subject simultaneouslywith the subject undergoing a surgical procedure.
 21. The method ofclaim 1, wherein the liquid unit dosage form is administered to thesubject within 24 hours after the subject has undergone a surgicalprocedure.
 22. The method of claim 1, wherein the administration isintravenous administration.
 23. The method of claim 1, wherein theadministration is intramuscular administration or subcutaneousadministration.
 24. The method of claim 1, wherein the pharmaceuticalcomposition is administered from a bag, a glass vial, or a prefilledsyringe.
 25. The method of claim 1, wherein the bag is a polymer bag,and optionally wherein the bag is further packaged in an aluminumover-pouch that optionally contains an oxygen scavenger.